CHAPTER 29
Extracellular Matrix Molecules
T his chapter introduces the macromolecules of the
extracellular matrix. Although the extracellular matrix is
composed of only five classes of macromolecules
collagens, elastin, proteoglycans, hyaluronan, and adhe-
sive glycoproteinsit can take on a rich variety of
different forms with vastly different mechanical proper-
ties. This is possible for two reasons. First, each of these
classes of macromolecule comes in a number of variants
(encoded by different genes or produced by alternative
splicing), each with distinctive properties. Second, the
cells that constitute the extracellular matrix secrete dif-
ferent proportions of these isoforms in various geometri-
cal arrangements. As a result, the extracellular matrix in
different tissues is adapted to particular functional
requirements, which vary widely in tendons, blood
vessel walls, cartilage, bone, the vitreous body of the
eye, and subcutaneous fat. Beyond providing mechani-
cal support, the extracellular matrix also strongly influ-
ences embryonic development, provides pathways for
cellular migration, provides essential survival signals, and
sequesters important growth factors.
Collagen
The collagen family is the most abundant and versatile
classes of proteins in the human body. Collagens form a
wide range of different structures with remarkable
mechanical properties. Weight for weight, fibrous
collagens are as strong as steel. Their name, which
comes from the Greek words for glue and produc-
ing, reflects the long-known adhesive properties of
denatured collagen extracted from animal tissues.
The defining feature of collagens is a rod-shaped
domain composed of a triple helix of polypeptides (Fig.
29.1). Each polypeptide folds into a left-handed polypro-
line II helix that repeats every third residue with the side
chains on the outside. Three of these helices associate
to form a triple helix that may be up to 420nm long.
The triple helical domains have a repeating amino acid
sequence: glycine-X-Y, where X is most often proline and
Y is most often hydroxyproline. The small glycine resi-
dues allow tight contact between the polypeptides in the
core of the triple helix. Larger residues, even alanine,
interfere with packing. Poly-L-proline has a strong ten-
dency to form a left-handed helix like individual collagen
chains but does not form a triple helix, owing to steric
interference. The triple helix is most stable if all X resi-
dues are proline and all Y residues are hydroxyproline,
A B C
Chain B
Y
Y G
G
X G
G
G
G
X
Chain A
X Chain C
FIGURE 29.1 COLLAGEN TRIPLE HELIX. A, End-on view of
three left-handed polyproline type II helices with glycines (G) in the
core. B, Longitudinal view of the strands of a triple helix. C, Space-
filling model of the structure of a short collagen triple helix. (A, Modified
from van der Rest M, Garrone A. Collagen family of proteins. FASEB
J. 1991;5:28142823. C, See Protein Data Bank [PDB; www.rcsb.org]
file 1BKV.)
505
506 SECTION VIII n Cellular Adhesion and the Extracellular Matrix

but other residues at some of these positions are essen-
tial for collagen to assemble higher-order structures.
Humans have approximately 100 genes with collagen
triple repeats, and more than 20 specialized collagen
proteins have been characterized (Fig. 29.2 and
Appendix 29.1). Most are components of the extracel-
lular matrix, but a few are transmembrane proteins
(see Fig. 31.8C). Collagen proteins were named with
Roman numerals in the order of their discovery. The
polypeptides are called -chains and numbered sepa-
rately. Appendix 29.1 groups collagens according to
function.
The size and shape of collagens vary according to
function. Some collagens are homotrimers of three iden-
tical -chains. Others are heterotrimers of two or three
different -chains. Some chains (eg, [1(II)]) are used in
more than one type of collagen.
Other proteins, including the extracellular enzyme
acetylcholine esterase (see Fig. 17.9) and some cell
surface receptors, have similar triple helical domains but
are not classified as collagens. To be a collagen, a protein
must also form fibrils or other assemblies in the extracel-
lular matrix. Nematodes, which lack connective tissue,
seem to have lost the genes for fibrillar collagens but
have elaborated a family of 160 genes for collagens that
form their cuticle.
Collagen biochemistry is challenging, because many
tissue collagens are insoluble, owing to covalent cross-
linking between proteins. Historic purification proto-
cols began with proteolytic digestion to liberate

MOLECULES AGGREGATES AGGREGATE MICROGRAPHS

A. Fibrillar collagens 100 nm

N
C

Types I, II, III, V, and XI

Overlaps Gaps

B. Sheet-forming collagens 7S
NC1
Tetramer ("spider")
NC1
7S NC1
N C
Type IV (NC1)2

7S

N C N C
Type X(?) Type VIII

C. Anchoring/linking collagens Dimer Tetramer

N C
Type VI
Beaded filament

AF
Dimer
NC1 NC1 NC1
N
C
Type VII Anchoring
fibril (Af) BL

NC4
N Type II
C NC4 collagen
GAG Type IX fibril
Type IX
N
C
Type XII and XIV

FIGURE 29.2 COMPARISON OF MAJOR COLLAGEN FAMILIES. Scale drawings and micrographs of collagen molecules and their assem-
bly into higher-order structures. AF, anchoring fibrils; BL, basal lamina; NC1, noncollagenous domain 1; NC4, noncollagenous domain 4; 7S, a
domain of type IV collagen. (Modified from van der Rest M, Garrone R. Collagen family of proteins. FASEB J. 1991;5:28142823.)

protease-resistant triple helical fragments. Now intact
collagens can be isolated after secretion by cells in tissue
culture.
Fibrillar Collagens
Triple helical rod-shaped collagen molecules about
300nm long self-associate to form strong but flexible
banded fibrils (Fig. 29.2) that reinforce all the tissues of
the body. Collagen fibrils form a variety of higher-order
structures. Loose connective tissue (see Fig. 32.1A) has
an open network of individual fibrils or small bundles of
fibrils that support the cells. In many tissues, the fibrils
of type I and associated collagens aggregate to form the
so-called collagen fibers that are visible by light micros-
copy (Fig. 29.3A). In extreme cases, such as in tendons,
the extracellular matrix consists almost exclusively of
tightly packed, parallel bundles of collagen fibers (see
Fig. 32.1B). In bone, type I collagen fibrils form regular
layers reinforced by calcium phosphate crystals (see Fig.
32.4). Layers of orthogonal collagen fibers make the
transparent cornea through which one sees (Fig. 29.3C).
In cartilage and the vitreous body of the eye, type II col-
lagen fibrils trap glycosaminoglycans and proteoglycans,
which retain enough water for the matrix to resist com-
pression (see Fig. 32.3) and, in the case of the eye, to
provide an optically clear path for light.
Fibrillar collagens are widespread in nature and have
been highly conserved during evolution, so the homo-
logs from sponges to vertebrates are similar. Each fibril-
lar collagen can form homopolymers in vitro; but in vivo,
most form heteropolymers with at least one other type
of fibrillar collagen (Appendix 29.1). This mix of the
fibrillar collagen subunits is one factor that regulates the
size of collagen fibers. Proteoglycans also participate in
regulating collagen assembly (Appendix 29.2).
Biosynthesis and Assembly of Fibrillar Collagens
The biosynthesis of collagen is noteworthy for the exten-
sive number of processing steps required to prepare the
A B
FIGURE 29.3 MICROGRAPHS OF COLLAGEN FIBRILS IN CONNECTIVE TISSUES. A, Collagen fibrils (pink) in the dense connective
tissue of the dermis. B, Electron micrograph of a thin section of a fibroblast, collagen fibrils, and elastic fibers. C, Orthogonal layers of collagen
fibrils in the cornea of the eye. (A, Courtesy D.W. Fawcett, Harvard Medical School, Boston, MA. B, Courtesy J. Rosenbloom, University of
Pennsylvania, Philadelphia. C, Courtesy E.D. Hay, Harvard Medical School, Boston, MA.)
CHAPTER 29 n Extracellular Matrix Molecules 507
protein for assembly in the extracellular matrix (Fig.
29.4). Fibroblasts synthesize type I collagen. Collagen
follows the exocytic pathway used by other secreted
proteins (see Chapter 21), but along the way it undergoes
several rounds of precise proteolytic cleavage, glycosyl-
ation, catalyzed folding, and chemical crosslinking. The
final product is a smooth fibril with staggered molecules
crosslinked to their neighbors. Other fibrillar collagens
are likely to be produced by similar mechanisms.
Large genes with 42 exons encode the -chains of
type I collagen. All the exons for the triple helical domain
were derived during evolution by duplication and diver-
gence from a primordial exon of 54 base pairs (bp)
coding for 18 amino acids or six turns of polyproline
helix. Approximately half of the exons consist of 54bp;
a few with 45bp have lost one Gly-X-Y; and the rest are
108 (2 54) or 162 (3 54)bp. Distinctive exons encode
the N- and C-terminal globular domains.
The initial transcript, referred to as preprocollagen,
translocates into the lumen of the rough endoplasmic
reticulum, where intracellular processing begins (Fig.
29.4). First, removal of the N-terminal signal sequence
yields procollagen with unfolded -chains with N- and
C-terminal nonhelical propeptides. Second, enzymes
hydroxylate most prolines and some lysines in the
Y-position. Third, enzymes add sugars (gal-glu or gal) to
the delta-carbon of some lysines, by a mechanism dis-
tinct from the typical glycosylation of asparagine or
serine (Fig. 3.26).
A novel mechanism initiates the folding of collagen in
the endoplasmic reticulum: the C-terminal propep-
tides of three -chains form a globular structure stabi-
lized by cysteines linked with disulfide bonds. The
enzyme protein disulfide isomerase catalyzes the for-
mation of these disulfides. Formation of this globular
domain has three important consequences. First, it
ensures the correct selection of -chains (two 1-chains
and one 2-chain in the case of type I collagen). Second,
it aligns the three polypeptides with their C-terminal
C
Fibroblast
Collagen
longitudinal
sections
Collagen
cross
sections
Elastic fiber
508 SECTION VIII n Cellular Adhesion and the Extracellular Matrix
A GlcGal
Gal
Chain selection
and registration
N
C
GlcGal
Gal
Folding
Folded procollagen
FIGURE 29.4 BIOSYNTHESIS AND ASSEMBLY OF FIBRILLAR COLLAGEN ILLUSTRATING DETAILS COVERED IN THE TEXT.
A, Translation of -chains, chain registration, and folding. B, Secretion, assembly, and crosslinking. (Modified from Prokop DJ. Mutations in col-
lagen genes as a cause of connective tissue diseases. N Engl J Med. 1992;326:540546. Copyright 1992 Massachusetts Medical Society. All
rights reserved.)
Gly-X-Y repeats in register, ensuring that the triple helix
forms with all three chains in phase. Third, the globular
propeptides prevent assembly of procollagen into insol-
uble fibrils during transit through the secretory pathway.
Given their repeating Gly-X-Y structure, separated col-
lagen chains without propeptides associate indiscrimi-
nately and out of register with other chains. For example,
gelatin is simply a mixture of collagen chains without
propeptides. Boiling dissociates the chains from each
other. When cooled, the chains randomly associate out
of register at random positions along their lengths,
forming a branching network that solidifies into the gel
that is used in food preparation.
Following selection and registration of the three
-chains, the helical rod domains zip together, beginning
at the C-terminus. Correct folding of the triple helix
requires all-trans peptide bonds. Because proline forms
cis and trans peptide bonds randomly, the slow isomeri-
zation of cis prolyl-peptide bonds to trans limits the rate
of triple helix folding in vitro. The enzyme prolyl-
peptide isomerase catalyzes the interconversion of
these prolyl-peptide bonds and speeds up folding of the
triple helix in vivo. The resulting rod-shaped, triple-helix
glycoprotein is called procollagen.
Procollagen is too large (>300nm long) to fit into
conventional COPII coated vesicles that bud from the
endoplasmic reticulum (ER) with cargo destined for the
Golgi apparatus (see Fig. 21.3), so accessory proteins are
required. These transmembrane proteins interact with
both procollagen inside the ER and the forming COPII
B
Proteolytic
trimming
Collagen
molecule
assembly
Crosslinking
coat on the cytoplasmic side of the membrane. They
allow the COPII vesicle to grow large enough to accom-
modate protocollagen. The COPII vesicles deliver proto-
collagen to the Golgi apparatus. Humans with mutations
in the gene for the COPII protein Sec23A have defects
in collagen secretion and bone formation.
Less is known about the path of procollagen through
the Golgi apparatus and vesicles that transport proto-
collagen to the cell surface, where it is secreted. Some
cells have specialized collagen assembly sites (Fig. 29.4).
Like a spider trailing its silk web behind, fibroblasts
help determine the arrangement of collagen fibrils as
they move through tissues (Fig. 29.3C). Outside the
cell, matrix metalloproteinases (Fig. 29.19) cleave the
propeptides from the triple helical domain, forming
the mature collagen molecule (formerly called
tropocollagen).
Relieved of its inhibitory propeptides, collagen self-
assembles into fibrils by a classical entropy-driven
process (Fig. 29.5). Weak, noncovalent bonds between
collagen molecules specify the self-assembly of fibrils but
provide little tensile strength. Adjacent collagen mole-
cules are staggered by 67nm, so a 35-nm gap is required
between the ends of the collagen molecules (5 staggers
at 67nm = 335nm = 1 molecular length of 300nm + a
35-nm gap). The size of the fibrils is influenced by incor-
poration of minor fibrillar collagens (eg, collagen V) and
interactions of FACIT (fibril-associated collagens with
interrupted triple helices) collagens and other matrix
molecules with their surfaces.
 CHAPTER 29 n Extracellular Matrix Molecules 509

The great tensile strength of mature collagen fibrils
comes from covalent crosslinking between the inex-
tensible triple helices. For most fibrillar collagens, the
enzyme lysyl oxidase catalyzes the formation of cova-
lent bonds between the ends of collagen molecules
(Figs. 29.4 and 29.6). The enzyme oxidizes the amino
groups of selected lysines and hydroxylysines to alde-
hydes. These aldehydes react spontaneously with nearby
lysine and hydroxylysine side chains to form a variety of
covalent crosslinks between two or three polypeptides.
Disulfide bonds, rather than modified lysine side chains,
crosslink type III collagen fibrils.
Point mutations or deletions in collagen genes or lack
of function of one of the enzymes that processes colla-
gen (lysyl hydroxylase, lysyl oxidase, or procollagen
proteases) can each cause defective collagen fibrils
(Appendix 29.1). These defects cause a number of
deforming and even lethal human diseases: brittle
bones (osteogenesis imperfecta), fragile cartilage (several
forms of dwarfism), and weak connective tissue (Ehlers-
Danlos syndrome). Chapter 32 discusses these diseases
in more detail.
organs, epithelia, or even whole animals. Six different
human genes for type IV collagen encode proteins that
form net-like polymers that assemble into the basal
lamina beneath epithelia (Fig. 29.7) and around muscle
and nerve cells. The concluding section of this chapter
provides details about basal lamina structure, function,
and diseases. Hexagonal nets of type VIII collagen form
a special basement membrane (Descemet membrane)
under the endothelium of the cornea. Related collagens
form the cuticle of earthworms and the organic skeleton
of sponges.
Linking Collagens
Specialized connecting and anchoring collagens (also
called FACIT) link fibrillar and sheet-forming collagens
EPIDERMAL CELL
IFs
Hemidesmosomes

Sheet-Forming Collagens
Basal
Collagens in this second group polymerize into sheets lamina
rather than fibrils (Fig. 29.2). These sheets surround Anchoring
fibrils

Gold-labeled
antibody to
type VII
collagen
DERMIS
64 nm
64 nm
64 nm
FIGURE 29.7 ANCHORING FIBRILS OF TYPE VII COLLAGEN.
Electron micrograph of a thin section of human skin reacted with a
gold-labeled antibody to the C-terminal domain of type VII collagen.
Top to bottom, Basal epithelial cell with keratin intermediate filaments
(IFs) attached to hemidesmosomes, which link to the basal lamina.
335 nm
Short fibrils of type VII collagen link the basal lamina to plaques in
FIGURE 29.5 STRUCTURE OF COLLAGEN FIBRILS. Electron the dermis. Both ends of these bipolar fibrils (Fig. 29.2) are labeled
micrographs and drawing of molecular packing. (Micrographs courtesy with gold. Bar is 0.1m. (Courtesy D.R. Keene, Portland Shriners
Alan Hodges, Marine Biological Laboratory, Woods Hole, MA.) Hospital, OR.)

Collagen chain 1 Hydroxypyridinium

Lysine Hydroxylysine crosslink

OH OH
C C
NH2 NH2 NH2
O H C C OH
C C
Oxidation by Condensation N
NH O H
lysyl oxidase C OH
OH OH

Hydroxylysine
Collagen chain 2

FIGURE 29.6 COVALENT CROSSLINKING OF COLLAGEN MOLECULES. After lysyl oxidase oxidizes hydroxylysine side chains, the
aldehydes condense with each other and a lysine to form two- and three-membered (shown) crosslinks between adjacent collagen molecules.
510 SECTION VIII n Cellular Adhesion and the Extracellular Matrix

to other structures (Fig. 29.2). For example, type VII

collagen forms anchoring fibrils that link of the type A
IV collagen in the basal lamina of stratified epithelia to
plaques in the underlying connective tissue (Fig. 29.7).
The type VII collagen homotrimer has an exceptionally
long triple-helix domain with nonhelical domains at the
N-terminus of each chain. The tails of type VII molecules
overlap to form antiparallel dimers that associate laterally
to form anchoring fibrils. Mutations in type VII collagen
cause both dominant and recessive forms of a severe
blistering disease, dystrophic epidermolysis bullosa.
In heterozygotes, mutated chains interfere with the
assembly of anchoring fibrils by normal type VII collagen
chains. Without anchoring fibrils, the basal lamina
adheres weakly to the connective tissue matrix. Even
mild physical trauma to the skin causes the epithelium
to pull away from the connective tissue, forming a
blister. Mutations in intermediate filaments cause similar
defects (see Fig. 35.6).
Type IX collagen heterotrimers do not polymerize. B
Endothelium
Instead, they associate laterally with type II collagen
fibrils with an N-terminal helical segment and a glycos- Internal elastic lamina
aminoglycan on a serine projecting from the surface (Fig.
29.2). In the vitreous body of the eye, these polysaccha- Smooth muscle
rides fill most of the extracellular space.

Elastic Fibers
Rubber-like elastic fibers are found throughout the
body and are prominent in the connective tissue of
skin, the walls of arteries (Fig. 29.8), and the lung. They
are entropic springs that recoil passively after tissues are
stretched. For example, each time the heart beats, pres-
surized blood flows into and stretches the large arteries.
Energy stored in elastic fibers pushes blood through the
FIGURE 29.8 ELASTIC FIBERS IN THE WALL OF A SMALL
circulation between heartbeats. ARTERY. A, Light micrograph of a cross section stained to bring out
Elastic fibers are composite materials; a network of the internal elastic lamina (box) and wavy elastic fibers among the
fibrillin microfibrils is embedded in an amorphous muscle cells. The boxed area includes the internal elastic lamina
core of crosslinked elastin, which makes up 90% of the between the endothelial cells lining the lumen and the underlying
smooth muscle cells. B, Electron micrograph of a longitudinal thin
organic mass (Fig. 29.9). Fibroblasts produce both com-
section illustrating the internal elastic lamina. In such standard prepara-
ponents. Loose bundles of microfibrils initiate assembly. tions, elastic fibers stain poorly and appear amorphous except for
A third protein, called fibulin, is required for elastin sub- occasional 10-nm microfibrils on the surface. (Courtesy Don W.
units to assemble between the microfibrils. Fawcett, Harvard Medical School, Boston, MA.)

A B

FIGURE 29.9 ELECTRON MICROGRAPHS OF DEVELOPING ELASTIC FIBERS FROM A FETAL CALF. A, Longitudinal section. B, Cross
section. Fibrillin microfibrils form a scaffolding for elastin, which stains darkly in this preparation. (Courtesy J. Rosenbloom, University of Pennsyl-
vania, Philadelphia.)
 CHAPTER 29 n Extracellular Matrix Molecules 511

Fibrillin is the primordial component of elastic fibers,
having arisen in Cnidarians (see Fig. 2.8). It is a long,
floppy protein consisting of a tandem array of domains
some of which are glycosylated (Fig. 29.10). Humans have
three fibrillin genes. Fibrillin-1 is the main component of
10-nm microfibrils, along with several glycoproteins.
Microfibrils are composed of parallel fibrillin molecules
that interact head to tail, reinforced by disulfide bonds
made by the first hybrid domains. Parts of neighboring
subunits overlap in globular beads connected by flexible
arrays of domains. Microfibrils are about 100 times stiffer
than elastin, and they stretch by rearrangement of mole-
cules and domains rather than unfolding. Fibrillins and
related proteins called latent-TGF (transforming growth
factor-)-binding proteins, act as repositories for TGF
family proteins in connective tissues.
Elastin subunits are a family of closely related 60-kD
proteins called tropoelastins, the products of alterna-
tive splicing from a single elastin gene. Long sequences
rich in hydrophobic residues are interrupted by short
sequences with pairs of lysines separated by two or three
small amino acids (Fig. 29.11). Lysine-rich sequences are
thought to form -helices with pairs of lysines adjacent
on the surface.
As tropoelastin assembles on the surface of elastic
fibers, lysyl oxidase oxidizes paired lysines of tropo-
elastin to aldehydes. Oxidized lysines condense into a
desmosine ring that covalently crosslinks tropoelastin
molecules to each other (Fig. 29.11). The four-way cross-
links, involving pairs of lysines from two tropoelastin
molecules, are unique to elastin. The same enzyme cata-
lyzes the crosslinking of collagen, but it forms only two-
and three-way crosslinks.
Elastic fibers are similar to rubber except that elastic
fibers require water as a lubricant. Hydrophobic seg-
ments between the crosslinks are thought to form exten-
sible random coils that extend and become aligned when
an elastic fiber is stretched (Fig. 29.11C). A difference
in entropy of the polypeptide in the contracted and
stretched states is thought to be the physical basis
for the elasticity (see the Gibbs-Helmhotz equation in
Chapter 4). Stretched fibers store energy, owing to
ordering (low entropy) of the polypeptide chains. Fibers
shorten when the resistance is reduced, because the

TB 8 cysteine EGF-like Calcium-binding Hybrid domains Proline-rich

EGF-like

FIGURE 29.10 DOMAIN ORGANIZATION OF HUMAN FIBRILLIN-1. A tandem array of independently folded domains, including 47 epi-
dermal growth factorlike (EGF-like) domains, forms a linear molecule. (Modified from Rosenbloom J, Abrams WR, Mecham R. Extracellular matrix
4: the elastic fiber. FASEB J. 1993;7:12081218.)

A C Contracted,
K
K
K
low energy,
K
K K
K K
K high entropy
K
K
K
K

K K
K K K K
K K K

B. Crosslinking reactions

Stretched,
CH2 C C high energy,
NH2
CHO CH2 NH2 NH CH2 CH2 N C CH2 low entropy
OHC CHO OHC CH2 N C C HN
CH2 C C
CHO CH Desmosine LNL CH2

FIGURE 29.11 ELASTIN POLYPEPTIDES AND CROSSLINKING REACTIONS. A, Lysine-rich helical domains separate random chains
rich in hydrophobic residues. BC, Lysyl oxidase converts lysine amino groups to aldehydes, which react with other lysines to form simple linear
crosslinks or six-membered rings linking two polypeptides. If the peptide bonds are hydrolyzed experimentally (not shown here), the linear crosslink
is released as leucyl-norleucine (LNL) and the six-membered crosslink is released as the amino acid desmosine. C, Comparison of the contracted
state with low-energy disordered chains having high entropy with the stretched state with high-energy ordered chains having low entropy. Elastin
polypeptides form a continuous, covalently bonded network. Application of force stretches the chains between the crosslinks. This is a low-
entropy, high-energy state. Reduced force allows the chains to contract into a more disordered, higher-entropy state with lower energy. (Modified
from Rosenbloom J, Abrams WR, Mecham R. Extracellular matrix 4: the elastic fiber. FASEB J. 1993;7:12081218.)
512 SECTION VIII n Cellular Adhesion and the Extracellular Matrix
polypeptide chains return to their disordered, lower-
energy, higher-entropy state.
Only embryonic and juvenile fibroblasts synthesize
elastic fibers, which turn over slowly, if at all, in adults.
Consequently, adults must make do with the elastic
fibers that are formed during adolescence. Fortunately,
these fibers are amazingly resilient. Arterial elastic fibers
withstand more than 2.5 billion cycles of stretching and
recoil during a human life. Many tissues become less
elastic with age, particularly the skin, which is subjected
to damage from ultraviolet irradiation. Compare, for
example, how readily the skin of a baby recoils from
stretching compared with that of an aged person. The
loss of elastic fibers in skin is responsible for wrinkles.
Dominant mutations in the elastin gene cause a human
disease called cutis laxa. The skin and other tissues of
patients with this disease lack resilience.
Collagens are found across the phylogenetic tree, but
only vertebrates are known to produce elastin. Inverte-
brates evolved two completely different elastic proteins.
Mollusks have elastic fibers composed of the protein
abductin. Insects use another protein, called resilin, to
make elastic fibers.
Dominant mutations in the fibrillin-1 gene cause
Marfan syndrome and illustrate the physiological func-
tions of elastic fibers. Most of the thousand known
fibrillin-1 mutations make the protein unstable and sus-
ceptible to proteolysis. Other point mutations interfere
with folding. All patients are heterozygotes.
Elastic fibers of patients with Marfan syndrome are
poorly formed, accounting for most of the pathological
changes. Most dangerously, weakness of elastic fibers
in the aorta leads to an enlargement of the vessel, called
an aneurysm, which is prone to rupture, with fatal con-
sequences. Prophylactic replacement of the aorta with
a synthetic graft and medical treatment with drugs
that block -adrenergic receptors (see Fig. 27.3) allow
patients a nearly normal life span. In some patients, a
floppy mitral valve in the heart causes reflux of blood
from the left ventricle back into the left atrium. Weak
elastic fibers that suspend the lens of the eye result in
dislocation of the lens and impaired vision. Weak elastic
fibers result in lax joints and curvature of the spine. Most
affected patients are tall, with long limbs and fingers, but
the connection of these features to fibrillin is not known.
The manifestations of the disease are quite variable, even
within one family, for reasons that are not understood.
Mutations in the fibrillin-2 gene cause congenital con-
tractural arachnodactyly, a disease characterized by joint
stiffness.
Glycosaminoglycans and Proteoglycans
Glycosaminoglycans (GAGs, formerly called mucopoly-
saccharides) are long polysaccharides made up of repeat-
ing disaccharide units, usually a hexuronic acid and a
hexosamine (Fig. 29.12). With one important exception
hyaluronanGAGs are synthesized as covalent, post-
translational modifications of a large family of proteins
called proteoglycans. These proteins vary in structure
and function, but their associated GAGs confer some
common features.
All vertebrate cells synthesize proteoglycans. Most
are secreted into the extracellular matrix, where they are
major constituents of cartilage, loose connective tissue,
and basement membranes. Mast cells package the pro-
teoglycan serglycin, along with other molecules in secre-
tory granules. A few proteoglycans, including syndecan
and CD44, are transmembrane proteins with their GAGs
exposed on the cell surface.
Of the known GAGs, hyaluronan (formerly called
hyaluronic acid) is exceptional in two regards. First,
enzymes on the cell surface synthesize the alternating
polymer of [D-glucuronic acid (1 3) D-N-acetyl glu-
cosamine (1 4)]n (Fig. 29.12). Other GAGs are syn-
thesized as posttranslational modifications of a core
protein. Second, hyaluronan is not modified postsyn-
thetically, as are all other GAGs. The linear polymer,
often exceeding 20,000 disaccharide repeats (a length
>20m) is released into the extracellular space.
In contrast to proteins, nucleic acids, and even
N-linked oligosaccharides, which are precisely deter-
mined macromolecular structures, the GAG chains of
proteoglycans appear to vary both in length and the
sequence of the sugar groups. The four-step synthesis of
GAGs (Fig. 29.12) explains this variability:
1. Ribosomes associated with ER synthesize the core
protein, which enters the secretory pathway.
2. In compartments between the ER and the trans-Golgi
apparatus, glycosyltransferases initiate GAG syn-
thesis by adding one of three different, short, link
oligosaccharides to serine or asparagine residues
of the core proteins (Fig. 29.12AB). The structural
clues identifying these sites are not understood, as
they do not have a common amino acid sequence
motif. A tetrasaccharide attached to serine anchors
dermatan sulfate, chondroitin sulfate, and heparan
sulfate. Branched oligosaccharides anchor keratan
sulfate to serine or asparagine.
3. In the trans-Golgi network, other glycosyltransferases
elongate the polysaccharide by adding, sequentially,
two alternating sugars to the growing chain (Fig.
29.12DF). The primary products are homogeneous,
linear polymers, each with one pair of alternating
sugars.
4. Enzymes modify some but not all the residues along
these alternating sugar polymers by adding sulfate to
hydroxyl or amino groups, or by isomerizing certain
carbons to convert D-glucuronic acid to its epimer
L-iduronic acid (Fig. 29.12DF). The result is a hetero-
geneous polymer. The mechanisms that select par-
ticular sites for modification are not understood.
 CHAPTER 29 n Extracellular Matrix Molecules 513

A CS U
3
N D. Chondroitin/Dermatan Sulfate
n 2 -1,4-glcUA-
U G G X O Ser
-1,3-galNAc-- SO3
4 SO3
HS U H -1,4-idoUA-
n HO
CO2 CH2OH
O 4 O 4 O
3 4
B S G H Direction of O 1 O
6
synthesis HO 3 1 3
NH
4
N O Ser (Thr) OH n
3 3 Ac
S G
KS S
3
G
4
H O-linked E. Keratan Sulfate
-1,3-gal--1,4-glcNAc-- SO3
3 4 2
HO
S G H M F O CH2OH
6 6 4 O
4 4
M H H N C Asn CH2OH
3 Direction of
S
3
G
4
H
2
M H synthesis O 3 1 O 4 O
OH
N-linked HO 1 O
3
NH
U Glucuronic acid S Sialic acid F Fucose F. Heparan Sulfate/Heparin Ac
n

G Galactose H glcNAc M Mannose -1,4-glcUA-

Phosphate X Xylose N galNAc -1,4-glcNAc--
-1,4-idoUA-
CO2 SO3
C. Hyaluronan O 4 O
-1,4-glcUA--1,3glcNAc-- Direction of CH2OH
synthesis HO 3 1 O 4 O
CO2 CH2OH OH
O 4 O HO 4 O
HO 1
3
NH
HO 1 O 3 1 O Direction of O
3
OH NH synthesis SO3 Ac n
n
Ac
FIGURE 29.12 SYNTHESIS OF GLYCOSAMINOGLYCANS (GAGS). AB, Three short oligosaccharides link GAGs (left) to proteoglycan
core proteins (right). A, A tetrasaccharide anchors chondroitin sulfate (CS), dermatan sulfate, and heparan sulfate (HS) to serine residues. B, Two
different, branched oligosaccharides link keratan sulfate (KS) to either serine or asparagine. CF, Four parent polymers and postsynthetic modi-
fications. C, Hyaluronan [D-glucuronic acid (1 3) D-N-acetylglucosamine (1 4)]n (n 25,000) is not modified postsynthetically. D, Chon-
droitin sulfate and dermatan sulfate are synthesized as [D-glucuronic acid (1 3) D-N-acetylgalactosamine (1 4)]n (n usually <250) and
then modified. Some N-acetylgalactosamines are sulfated. In dermatan sulfate, D-glucuronic acids are epimerized to L-iduronic acid. E, Keratan
sulfate is synthesized as [D-galactose (1 4) D-N-acetylglucosamine (1 3)]n (n usually = 2040) and then modified by sulfation. F, Heparan
sulfate/heparin is synthesized as [D-glucuronic acid (1 4) D-N-acetylglucosamine (1 4)]n (n usually <100) and then modified by sulfation
and by epimerization of D-glucuronic acid to L-iduronic acid. galNAc, N-acetylgalactosamine; glcNAc, N-acetylglucosamine. (Modified from Wright
TN, Heinegard DK, Hascall VC. Proteoglycans, structure and function. In Hay ED, ed. Cell Biology of the Extracellular Matrix, 2nd ed. New York:
Plenum Press; 1991:4578.)

The present nomenclature for proteoglycans is based Types IX and XII have chondroitin sulfate chains, and
on the core protein. The historic nomenclature based on type XVII has heparin sulfate chains.
the identity of the GAGs was imprecise, as more than The number of GAGs attached to the core protein
one type of proteoglycan can carry the same GAG. The varies from one (decorin) to more than 200 (aggrecan)
weakness of the new system is that the protein name (Fig. 29.13). A particular core protein can have identical
reveals nothing about the associated GAGs. This informa- (fibroglycan, glypican, versican) or different (aggrecan,
tion is important, because various cells add different serglycin, syndecan) types of GAGs. Some cell types add
GAGs to the same core protein or can modify the same different GAGs to the same core protein or secrete a core
GAG in different ways. protein without GAGs.
Cells secrete many proteoglycans into the extracel- Given their physical properties and distribution
lular matrix, but they retain some types on the plasma among the fibrous elements of the extracellular matrix,
membrane through transmembrane polypeptides or a proteoglycans and hyaluronan are thought to be elastic
glycosylphosphatidylinositol anchor (Appendix 29.2 and water-trapping space fillers. Each hydrophilic disaccha-
Fig. 29.13). The core proteins vary in size from 100 to ride unit bears a carboxyl or sulfate group or both, so
4000 amino acids. Many are modular, consisting of famil- GAGs are highly charged polyanions that extend them-
iar structural domains found in epidermal growth factor selves by electrostatic repulsion in solution and attract
(EGF), complement regulatory protein, leucine-rich up to 50g of water per gram of proteoglycan. Hyaluro-
repeats, or lectin. Three collagens carry GAG side chains: nan, the largest GAG, occupies a vast volume. A single
514 SECTION VIII n Cellular Adhesion and the Extracellular Matrix

Aggrecan
Hyaluronan

G1 G2 G3
N C

KS-rich
region
insert

Decorin Serglycin Perlecan Syndecan

N C
Leucine-rich N
repeats N
C

N C
Glypican
N-linked oligo
KS (ser/thr)
CS/DS (ser/gly) N
C GPI
HS/Hep (ser/gly) anchor

FIGURE 29.13 SCALE DRAWINGS OF A VARIETY OF PROTEOGLYCANS. Core proteins are purple except for the red leucine-rich repeats
of decorin and the glycosaminoglycans are color-coded. Proteins were named according to the following: aggrecan aggregates along hyaluronan;
decorin decorates collagen fibrils; perlecan resembles a string of pearls; serglycin has 24 Ser-Gly repeats; syndecan (syndein = link) links cells to
the matrix; glypican has a glycosylphosphatidylinositol (GPI) membrane anchor. CS, chondroitin sulfate; DS, dermatan sulfate; Hep, heparin; HS,
heparan sulfate; KS, keratan sulfate. (Modified from Wright TN, Heinegard DK, Hascall VC. Proteoglycans, structure and function. In Hay ED, ed.
Cell Biology of the Extracellular Matrix, 2nd ed. New York: Plenum Press; 1991:4578.)

hydrated molecule of 25,000kD has a diameter of
200nm, larger than a synaptic vesicle. Retention of
water by hyaluronan and aggrecan-keratan sulfate/
chondroitin sulfate proteoglycan is essential for the
mechanical properties of cartilage (see Fig. 32.3). In the
extracellular matrix of other tissues, networks of densely
charged hyaluronan restrict water flow, limit diffusion of
solutes (especially macromolecules), and impede the
passage of microorganisms. Hyaluronan and proteogly-
cans also act as lubricants in joint cavities and as an
optically transparent, space-filling medium in the vitre-
ous body of the eye. Exceptionally high concentrations
of hyaluronan in the tissues of subterranean naked mole
rats seem to protect them from cancer and give them
life spans much longer than any other rodent. The mech-
anism is not known.
Beyond these mechanical functions, proteoglycans
influence cellular behavior such as adhesion or motility.
Transmembrane proteoglycans can link cells to fibronec-
tin and connective tissue collagens. Syndecan provides
a particularly clear example. Lymphocytes express syn-
decan twice: early in their maturation, when they adhere
to matrix fibers in the bone marrow, and later, when, as
mature plasma cells, they adhere to the matrix of lymph
nodes. In between, syndecan expression is lower while
the lymphocytes circulate in the blood.
Carefully regulated expression allows proteoglycans
to influence embryonic development and wound healing
in at least three different ways. First, both decorin
and fibromodulin regulate assembly of collagen fibrils.
Second, many polypeptide growth factors (including
platelet-derived growth factor and TGF) bind to proteo-
glycans in the extracellular matrix. This allows the matrix
to concentrate circulating growth factors at specific
locations and to release them locally over time. Third,
membrane-bound proteoglycans, including syndecan
and glypican, act as coreceptors for growth factors.
The well-known anticoagulant effects of heparin and
heparan sulfate are attributable to their ability to bind
both thrombin (the proteolytic enzyme that converts
fibrinogen to fibrin) and a thrombin inhibitory protein.
This promotes interaction of the inhibitor with thrombin
and inactivates the clotting cascade. A short sequence of
five modified sugars has the anticoagulant activity.
Adhesive Glycoproteins
In principle, the macromolecules of the extracellular
matrix and the constituent cells might interact relatively
nonspecifically, but the evidence suggests that specific
molecular interactions mediate most of the interactions
that organize the matrix and the associated cells. Most

interactions are between proteins, but some are between
proteins and sugars. Although some of these interactions
are direct (with some cell surface receptors binding col-
lagen directly), adapters called adhesive glycoproteins
mediate many of the interactions (Appendix 29.3).
Adhesive glycoproteins were discovered by using bio-
chemical assays for factors that favor particular interac-
tions, such as adherence of cells to a matrix component.
Further work revealed that adhesive glycoproteins are
more than molecular glue; they also provide cells with
signals required for the development and repair of
tissues. Cells receive these signals when they bind to
the matrix components. Chapter 30 focuses on their
receptors.
Adhesive glycoproteins provide specific molecular
interactions in the matrix by binding to cells, matrix
macromolecules, or both. Adhesive proteins with mul-
tiple binding sites for cell surface receptors link cells
together. For example, fibrinogen aggregates platelets
during blood clotting (see Fig. 30.14). Other adhesive
proteins link cells to the extracellular matrix. Thus, fibro-
nectin mediates the attachment of cells to fibrin and
collagen (Fig. 29.14). A third group of adhesive proteins
links matrix macromolecules together. For instance,
nidogen attaches laminin to collagen and link protein
attaches aggrecan-proteoglycan to hyaluronan.
The repertoire of adhesive proteins extends far
beyond the number of named proteins (Appendix 29.3).
Multiple genes or, more commonly, alternative splicing
of the product of a single gene (see Fig. 11.6), generate
multiple, functionally distinct isoforms of most of the
proteins. Particular isoforms are often expressed in spe-
cific tissues at predictable times during development.
Most adhesive glycoproteins are constructed of a
series of compact modules (see Fig. 3.13 and Appendix
29.3). During evolution, duplication and recombination
of the coding sequences for these domains produced the
FN I FN II FN III
Crosslinking Matrix
site Fibrin assembly
N F1 F2 F1
Matrix Collagen
assembly Gelatin
Heparin
FIGURE 29.14 DOMAIN ORGANIZATION OF FIBRONECTIN. A linear array of FN-I (45 residues), FN-II (45 residues), and FN-III (90 residues)
domains forms a rod-shaped subunit. Disulfide bonds near the C-termini covalently link two identical subunits in the dimeric molecule. Ligand-
binding sites are indicated. The FN-III domain 10 contains the RGD (arginine-glycine-aspartic acid) sequence that binds cell surface integrins.
Binding sites for fibrin, collagen, and glycosaminoglycans are indicated. Alternative splicing at sites ASRB, ASRA, and ASRC creates different
isoforms. (For reference, see PDB files 1PDC and 1FNA and Potts JR, Campbell ID. Fibronectin structure and assembly. Curr Opin Cell Biol.
1994;6:648655.)
CHAPTER 29 n Extracellular Matrix Molecules 515
genes encoding these large proteins. In addition to the
familiar domains, each of these proteins also contains a
significant fraction of unique sequences.
Heterodimeric transmembrane receptors called inte-
grins bind most adhesive glycoproteins that interact
with cells (see Fig. 30.9). Remarkably, the integrin-
binding sites of many adhesive proteins include the
simple tripeptide arginine-glycine-aspartic acid (RGD;
Fig. 29.14), which acts as a universal zip code.
Establishing the biological functions of adhesive gly-
coproteins is challenging because of their overlapping
functions and large sizes. Initial hypotheses were based
on the identification of binding partners and the time
and place of expression of each protein. Later, antibod-
ies or peptides were used to disrupt specific molecular
interactions in live organisms. Disruption of the gene
for each protein or its receptors provides definitive data,
and the consequences can be surprising. Some pheno-
types proved to be milder than expected from earlier
studies. These results argue that the adhesive glycopro-
teins function as a complementary system with partially
overlapping functions. Two examples illustrate what we
know about adhesive glycoproteins.
Fibronectin
Fibronectins are large proteins composed of two poly-
peptides of approximately 235kD linked by disulfide
bonds near their C-termini (Fig. 29.14). In electron
micrographs, fibronectin appears as a V-shaped pair of
long, flexible rods connected at one end. In solution, the
molecule is probably more compact. Each polypeptide
is a linear array of three types of domains called FN-I,
FN-II, and FN-III (for fibronectin-I, -II and -III). All three
types of fibronectin domains consist of antiparallel
strands with conserved residues in their hydrophobic
cores. Two disulfide bonds stabilize FN-I and FN-II
domains, whereas FN-III domains have no disulfide
Fibronectin dimer
Cell
ASRB ASRA ASRC
RGD
F3 F1 C
Cell Heparin Fibrin
Chondroitin
sulfate
516 SECTION VIII n Cellular Adhesion and the Extracellular Matrix
bonds. FN-I and FN-II domains consist of approximately
45 residues; FN-III domains are twice as large. FN-I and
FN-II domains are present in a few other proteins,
whereas the human genome contains about 170 genes
with FN-III domains, including proteins in the extracel-
lular matrix (Appendix 29.3), on the cell surface (human
growth hormone receptor; see Fig. 24.6), and inside cells
(titin; see Fig. 39.7).
Fibronectin binds a variety of ligands, including cell
surface receptors, collagen, proteoglycans, and fibrin
(another adhesive protein). Thus, it contributes to the
adhesion of cells to the extracellular matrix, guides the
assembly of collagens and fibrillins and may also cross-
link matrix molecules. The RGD sequence that contrib-
utes to binding integrins is on an exposed loop of FN-III
domain 10, but some binding sites are exposed only
when the protein is stretched. The variably spliced V
domain included in plasma fibronectin has a second
integrin-binding site. Chapter 30 provides additional
details on integrins.
Two pools of fibronectin have different distributions
and solubility properties. Tissue fibronectin forms insol-
uble fibrils in connective tissues throughout the body,
especially in embryos and healing wounds. Fibroblasts
use an integrin-dependent process to assemble fibronec-
tin dimers into fibrillar aggregates large enough to visual-
ize by light microscopy (Fig. 29.15). Denaturing agents
and disulfide reduction are required to solubilize these
fibrils. Fibronectin fibrils seem to bind cells more
A many embryonic tissues, wounds, and tumors. The
B found in an invertebrate. Vertebrates have maintained
FIGURE 29.15 FLUORESCENCE MICROGRAPHS OF FIBRO-
NECTIN NETWORKS IN TISSUE CULTURE. A, This fibroblast
expressed fibronectin-YFP (fibronectin fused to yellow fluorescent
protein, appearing yellow-green) and moesin-CFP (moesin fused to
cyan fluorescent protein, appearing red). The fibronectin assembled
an extracellular network. Moesin is associated with actin filaments in
stress fibers. B, Lower magnification of a fibronectin network. (Cour-
tesy T. Ohashi and H.P. Erickson, Duke University, Durham, NC.)
efficiently than soluble fibronectin, and may have addi-
tional activities important for biological functions.
Soluble plasma fibronectin dimers circulate in the
body fluids. The protein differs from tissue fibronectin
as a result of alternate splicing of the messenger RNA
(mRNA). In blood clots, the enzyme transglutaminase
covalently couples plasma fibronectin to fibrin, forming
a provisional matrix for wound repair (see Fig. 32.11).
Early embryos form an initial extracellular matrix from
fibronectin that is replaced by collagen as the embryo
matures. Embryonic cells, such as neural crest cells (pre-
cursors of pigment cells, sympathetic neurons, and
adrenal medullary cells), migrate along tracks in the
extracellular, fibronectin-rich matrix. Antibodies or fibro-
nectin fragments that interfere with the adhesion of cells
to fibronectin inhibit neural crest cell migration, gastrula-
tion, and the formation of many embryonic structures
derived from mesenchymal cells.
Surprisingly, mouse embryos without fibronectin can
develop almost normally up to about day 8 (when the
basic body plan is already determined). Thereafter homo-
zygous null mutant mice die from defects in mesodermal
structures, including the notochord, muscles, heart, and
blood vessels. Mice with null mutations in the main
fibronectin receptor, integrin 5, have similar but slightly
milder defects. Other adhesive glycoproteins and recep-
tors must compensate for fibronectin during the first few
days of development.
Tenascin
Tenascins are a family of four giant proteins with six
arms (Fig. 29.16), found in the extracellular matrix of
N-terminal ends of three subunits self-associate in a triple
helical coiled-coil. Disulfides covalently link two of these
three-chain units to make the hexameric molecule. The
arms of the four isoforms consist of different numbers
of EGF and FN-III domains, terminated by three similar
FN-III domains and a fibrinogen-like domain. The expres-
sion of tenascins-C, -R, -W, and -X hardly overlap in
adult tissues.
All vertebrates express tenascin, but it has yet to be
the tenascin genes over hundreds of millions of years,
and each isoform is expressed selectively in embryonic
tissues, so it was surprising that mice with disrupted
tenascin-C or tenascin-R genes are viable. However,
careful analysis showed that both have defects in their
brains and responses to injury. Tenascin-C null mice also
have defects in their lungs and stem cell compartments.
Genetic deficiency of tenascin-X causes Ehlers-Danlos
syndrome, a human condition with hyperextensible skin
and lax joints that is most often caused by mutations in
collagen type V gene.
Tenascins bind to fibronectin, integrins, proteogly-
cans, and immunoglobulin-superfamily receptors on the

A EGF domain B C. Tenascin-R (chicken, mouse)
Universal FN-III
domain
Alternatively spliced
FN-III domain
TN-C
TNfbg domain
D. Tenascin-C (human, pig, mouse, chicken, newt)
SS
N
E. Tenascin-X (human)
SS
N
FIGURE 29.16 DOMAIN ORGANIZATION OF THE THREE ISOFORMS OF TENASCIN. A, Domains. TNfbg, fibrinogen-like domain.
B, Electron micrograph of tenascin-C. C, Tenascin-R. D, Tenascin-C. E, Tenascin-X. Each of these tenascin molecules has six identical chains.
One is shown in its entirety. Five chains are represented only by a few of their N-terminal EGF domains. (Courtesy H.P. Erickson, Duke University,
Durham, NC.)
cell surface. Depending on the cell and the experimental
situation, tenascin can promote or inhibit adhesion of
cells to various substrates. This may contribute to spread-
ing of cancer cells.
Basal Lamina
The basal lamina, a thin, planar assembly of extracellular
matrix proteins, supports all epithelia, muscle cells, and
nerve cells outside the central nervous system (Fig.
29.17). This two-dimensional network of protein poly-
mers forms a continuous rug under epithelia and a sleeve
around muscle and nerve cells. In addition, basal laminae
can act as semipermeable filters for macromolecules, a
particularly important role that they play in the conver-
sion of blood plasma into urine in the kidney. The genes
for basal lamina components are very ancient, having
arisen in early metazoans.
In electron micrographs of thin sections of tissues
prepared by chemical fixation, the basal lamina is a
homogenous, finely fibrillar material close to the plasma
membrane (Fig. 29.17D). Collagens type VI, VII, XV, and
XVIII connect the lamina to the underlying connective
tissue. The basal lamina and associated collagen fibrils
form the basement membrane that is observed in his-
tologic preparations of epithelia. A basal lamina alone
cannot be seen by light microscopy without special
labels, such as those used in Fig. 29.17A and C.
Although many proteins contribute to the stability
of the basal lamina (Fig. 29.18), only the adhesive glyco-
protein laminin is essential for the initial assembly of
basal laminae during embryogenesis. The C-terminal end
CHAPTER 29 n Extracellular Matrix Molecules 517
Shared
SS C
N (One of 6 arms
displayed in full)
C
C
of the cross-shaped laminin molecule binds to cell surface
receptors (integrins, see Fig. 30.9; dystroglycan; see
Fig. 39.17). Laminins self-assemble into continuous, two-
dimensional networks through noncovalent interactions
of their short arms. Mouse embryos that lack dystrogly-
can or laminin die early in development, owing to failure
to make basal laminae.
The subsequent addition of other proteins reinforces
the laminin network. A two-dimensional network of col-
lagen IV self-assembles through head-to-head interac-
tions of the N-termini of four molecules and tail-to-tail
interactions of the C-terminal NC1 domains of two mol-
ecules (Fig. 29.2). The networks of both laminin and
collagen IV lie relatively parallel to the cell surface.
Mouse embryos that lack collagen IV make nascent basal
laminae composed of laminin but eventually die from
defects in basal lamina functions.
Other proteins reinforce the collagen IV and laminin
in basal laminae. The rod-shaped protein nidogen cross-
links laminin to type IV collagen. Perlecan, a heparan
sulfate proteoglycan, provides additional crosslinks. It
binds to itself in addition to laminin, nidogen, and col-
lagen IV. These crosslinks help determine the porosity
of the basal lamina and thus the size of molecules that
can filter through it. Fibrillin and an associated protein,
fibulin, are also present.
Epithelial and muscle cells secrete laminin and the
other components of basal lamina. Two different cells
can cooperate to produce a basal lamina between two
tissues. For example, epithelial cells make laminin, and
mesenchymal cells contribute nidogen to the same basal
lamina.
518 SECTION VIII n Cellular Adhesion and the Extracellular Matrix

SCHWANN
A B E CELL

AXON
BLOOD

CONNECTIVE TISSUE

C D

MUSCLE

NEURON

FIGURE 29.17 MICROGRAPHS OF THE BASAL LAMINA. A and C, Fluorescence micrographs of tissue sections stained with fluorescent
antibodies to type IV collagen, a major component of basal laminae. A, Kidney with basal laminae around the tubules and blood vessels, including
those of the glomerulus in the center. C, Skeletal muscle with basal laminae around the muscle cells. B, D, and E, Electron micrographs of thin
sections showing basal laminae (colored pink). B, Endothelial cell lining a blood vessel with a platelet in the lumen. D, Neuromuscular junction.
E, Unmyelinated nerve with numerous axons (yellow) surrounded by invaginations of Schwann cells (blue). (A and C, From Odermatt BF, Lang
AB, Ruttner JR, etal. Monoclonal antibody to human type IV collagen. Proc Natl Acad Sci U S A. 1984;81:73437347. B and E, Courtesy Don
W. Fawcett, Harvard Medical School, Boston, MA. D, Courtesy J. Heuser, Washington University, St. Louis, MO.)

attach to the underlying basal lamina, which is, in turn,

Nidogen Laminin Type IV collagen Perlecan
FIGURE 29.18 MOLECULAR MODEL OF THE BASAL LAMINA.
The drawing shows the sizes and shapes of the component molecules
and their postulated three-dimensional arrangement in the basal
lamina. (From Yurchenco P, Cheng YS, Colognato H. Laminin forms
an independent network in basement membranes. J Cell Biol.
1992;117:11191133.)
The interwoven network of protein fibers provides
the physical basis for the two main functions of the basal
lamina: mechanical support and selective permeability.
The basal lamina is a scaffold that anchors epithelial,
muscle, and nerve cells. In epithelia, all the basal cells
attached to the underlying connective tissue. Thus, force
applied to an exposed epithelial surface, such as skin, is
transmitted through the basal lamina to the connective
tissue. Similarly, all epithelial cells in tubular structures,
such as blood vessels and glands, adhere to a cylindrical
basal lamina that contributes to the integrity of the
tube. In muscle, the basal lamina around each cell
transmits the contractile forces between cells and
to tendons.
The fibrous network in the basal lamina also acts as a
filter for macromolecules and a permeability barrier for
cellular migration. In kidney, a basal lamina sandwiched
between two sheets of epithelial cells filters the blood
plasma to initiate the formation of urine. The molecular
weight threshold for the filter is approximately 60kD,
so most serum proteins are retained in the blood, whereas
salt and water pass into the excretory tubules. The high
charge of basal lamina proteoglycans contributes to
filtering by electrostatic repulsion. Basal laminae also
confine epithelial cells to their natural compartment. If
neoplastic transformation occurs in an epithelium, the
basal lamina prevents the spread of the tumor until
matrix metalloproteinases (see Matrix Metalloprotein-
ases below) break down the basal lamina.
The major basement membrane type IV collagen
consists of two 1(IV) chains and one 2(IV) chain. No
 CHAPTER 29 n Extracellular Matrix Molecules 519

A. Domain architecture
TABLE 29.1 Inherited Diseases or Mutant N C
Phenotypes of Basal Lamina Components Matrilysin MMP-7
Stromelysin 1 MMP-3
Protein Subunit Distribution Disease or Mutant Phenotype Gelatinase A MMP-2
Collagen 3IV Many Human autoantibodies cause Gelatinase B MMP-9
tissues Goodpasture syndrome of TM Stromelysin-3 MMP-11
renal failure.
MT1-MMP MMP-14
Collagen 5IV Kidney, Human mutation causes Alport
Linker Cytoplasmic
Signal peptide
muscle syndrome of renal failure. Hemopexin- domain
Propeptide like domain
Laminin 1 Many Fly null mutation is lethal Stretch with
Catalytic Fibronectin furin-recognition
tissues during embryogenesis. domain type II domain sequence
Laminin 2 Muscle, Mouse dy mutation causes
heart muscular dystrophy. B. ProMMP-2 structure
Laminin 2 Epidermis Human mutation causes
Herlitz junctional Catalytic
epidermolysis bullosa. domain Fibronectin
type II
Perlecan Many Worm unc-52 mutation domain 2
tissues disrupts myofilament Propeptide
attachment to membrane. Fibronectin
type II
domain 1
C
human mutations in the two major type IV collagen Fibronectin
type II
genes have been observed, presumably because they are domain 3
N
lethal, as observed in Drosophila.
Restricted human tissues express four additional type Hemopexin
domain
IV collagens. Remarkably, each has been implicated in
human disease (Table 29.1). More than 200 different
FIGURE 29.19 MATRIX METALLOPROTEINASE (MMP)
point mutations and deletions in the 5(IV) collagen STRUCTURES. A, Domain organization of MMP isoforms. All have
gene cause Alport X-linked familial nephritis. These an N-terminal cleaved signal sequence, a propeptide that binds to the
mutations interfere with folding of the collagen mole- active site and inhibits the protease activity, and a catalytic domain.
cule and disrupt the basement membranes that form Gelatinases have fibronectin (FN)-II domains inserted in the catalytic
the blood filtration barrier in the glomerulus of the domain. Matrilysin lacks the C-terminal domain. MMP-14 has a trans-
membrane segment near its C-terminus. B, Atomic structure of
kidney, causing progressive kidney failure. They also MMP-2 showing the arrangement of the domains and the propeptide
cause defects in the eye and ear, other places where the occupying the active site. (For reference, see PDB file 1CK7.)
5(IV) collagen gene is expressed. Patients with autoso-
mally inherited Alport syndrome have mutations in their
3(IV) or 4(IV) collagen genes. In Goodpasture syn- extracellular matrix contributes to degenerative diseases,
drome, the immune system produces autoantibodies to such as emphysema and arthritis. In addition to their
the C-terminal NC1 domain of 3(IV) collagen. The roles in remodeling, many of these enzymes cleave and
protein sequences that elicit autoantibody production release biologically active fragments from matrix or
are buried in the NC1 domain, so they may be exposed membrane proteins. Three classes of Zn-dependent pro-
by bacterial infections or organic solvents, predispos- teases account for both the physiological and pathologi-
ing events that trigger the syndrome. Antibodies bound cal degradation of diverse extracellular matrix and cell
to basement membranes in the kidney and lung cause surface proteins.
inflammation that leads to kidney failure and bleeding in The first class is called matrix metalloproteinases
the lungs. (MMPs). These 24 homologous enzymes share a zinc-
protease domain (Fig. 29.19) similar to bacterial thermo-
lysin. All have an N-terminal signal sequence and are
Matrix Metalloproteinases processed through the secretory pathway. Between the
Many physiological processes depend on the controlled signal sequence and catalytic domain, all MMPs have
degradation of the extracellular matrix. Examples include an autoinhibitory propeptide, including a conserved
tissue remodeling during embryogenesis (eg, resorption cysteine that binds to the zinc ion in the catalytic
of a tadpole tail), wound healing, involution (massive site. Most MMPs have a C-terminal regulatory domain
shrinkage secondary to loss of cells and extracellular that influences the substrate specificity of the catalytic
matrix) of the uterus after childbirth, shedding of the domain. Some MMPs have three FN-II domains inserted
uterine endometrium during menstruation, and invasion into the sequence of the catalytic domain (Fig. 29.10B).
of the uterine wall by the embryonic trophoblast during Most inactive pro-MMPs are secreted and then bind
implantation. Conversely, uncontrolled destruction of directly or indirectly to cell surface receptors. However,
520 SECTION VIII n Cellular Adhesion and the Extracellular Matrix
several MMPs are anchored to the plasma membrane by
a C-terminal transmembrane domain or a glycosylphos-
phatidylinositol tail.
MMP activity is carefully regulated at three levels,
normally restricting proteolysis to sites of tissue remodel-
ing or physiological breakdown. First, only particular
connective tissue, inflammatory, and epithelial cells are
genetically programmed to express MMP genes and to
respond to growth factors and cytokines to increase
production under appropriate circumstances. Second,
autoinhibited MMPs on the cell surface require propep-
tide cleavage for activation. Proteolytic cleavage and dis-
sociation of the propeptide activate the enzyme. Cellular
movements then deliver the active protease to specific
substrates. For example, membrane-anchored MMP-14
directly activates MMP-2, which then degrades basement
membrane collagen and other substrates. Third, secreted
proteins called tissue inhibitors of metalloprotein-
ases (TIMPs) and the plasma protein 2-macroglobulin
bind to the active site of MMPs, keeping their activity
in check.
Each MMP is selective for targets in the extracellular
matrix. In some cases, proteolysis disrupts the mechani-
cal integrity of the matrix. In others, cleavage of a col-
lagen isoform or other matrix protein releases a fragment
that favors or inhibits the formation of blood vessels. For
example, the N-terminal domain cleaved from collagen
XVIII is an inhibitor of angiogenesis that is called end-
ostatin. Mice survive null mutations in any one of several
MMPs tested, but the loss of an MMP may alter the sus-
ceptibility to disease dramatically. Mice without MMP-12
(macrophage elastase) are resistant to cigarette smoke,
which causes emphysema in normal mice. Without
MMP-12, smoke fails to stimulate elastin degeneration,
which weakens lung tissue and mediates inflammation.
MMPs contribute to the spread of tumors in mice,
but disappointingly small-molecule inhibitors of MMPs
have not proven useful for treatment of advanced tumors
in humans.
The second class of Zn-dependent proteases consists
of approximately 20 proteases called ADAMs (a disinte-
grin and metalloproteinase). These enzymes are anchored
to the plasma membrane by a single transmembrane
domain. Like other metalloproteinases, they are inhib-
ited by TIMPs. ADAMs cleave and release extracellular
domains of cell surface proteins, some of which are
important informational molecules (eg, tumor necrosis
factor [TNF]-; transforming growth factor [TGF]-).
ADAM-17 null mutations are lethal during embryogene-
sis, owing to a lack of TGF- or other ligands for EGF
receptors. A polymorphism in the ADAM-33 gene is asso-
ciated with some types of human asthma, although the
mechanism is not understood.
A third class of Zn-dependent proteases is called
ADAMTS, ADAMs with a thrombospondin domain.
These secreted proteases cleave specific matrix sub-
strates, such as the cartilage proteoglycan aggrecan.
Experiments with mice show that inactivation of the
protease domain of ADAMTS5 reduces the development
of the common joint disease osteoarthritis.
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 CHAPTER 29 n Extracellular Matrix Molecules 521

APPENDIX 29.1

Collagen Families
Type Chains Assembly Interactions Distribution Disease Mutations
Fibrillar Collagens
I 1.1.2(I) Fibrils Self; types III and V Bone, tendons, Osteogenesis imperfecta; Ehlers-
collagen; types XII ligaments, skin, Danlos syndrome type VII; Kniest
and XIV collagen dentin dysplasia; Stickler syndrome
II [1(II)]3 Fibrils Self; type IX and XI Hyaline cartilage, Spondyloepiphyseal dysplasia;
collagen vitreous body hypochondrogenesis;
achondrogenesis; Kniest
dysplasia; Stickler syndrome
III [1(III)]3 Fibrils Self; type I collagen Skin, blood vessels Ehlers-Danlos syndrome type IV
V 1.1.2(V) Fibrils Self; type I collagen Fetal membranes, Ehlers-Danlos syndrome
1.2.3(V) skin, bone, placenta,
synovial membranes
XI 1(XI)2(XI)1(II) Fibrils Self; type II collagen Hyaline cartilage Sticklers syndrome
Sheet-Forming Collagens
IV 1.1.2(IV) Nets Self; perlecan Basement membranes Autoantigen in Goodpasture
3.4.5(IV) laminin, nidogen, syndrome; 3(IV), 4 (IV), &
5.5.6(IV) integrins 5(IV) mutated in Alport
nephritis & porencephaly
VIII [1(VIII)]? Hexagonal net Self Descemet membrane Posterior polymorphous corneal
[2(VIII)]? (cornea) dystrophy
X [1(X)]3 ? ? Hypertrophic cartilage Schmid metaphyseal
chondrodysplasia
Connecting and Anchoring Collagens (Fibril-Associated Collagens With Interrupted Triple Helices [FACIT])
VI 1.2.3(VI) Beaded fibrils Self; type IV Vessels, skin, Bethlem myopathy, atopic
collagen intervertebral disk dermatitis
VII [1(VII)]3 Anchoring fibril Self; type IV Epidermaldermal Dystrophic epidermolysis bullosa
collagen junction
IX 1.2.3(IX) Linker Covalent GAG; type Hyaline cartilage, Multiple epiphyseal dysplasia
II collagen vitreous body
XII [1(XII)]3 ? Linker GAG; type I Embryonic tendon, Not known
collagen skin
XIV [1(XIV)]3 ? Linker GAG; ? type I Fetal tendon, skin Not known
collagen
XVIII [1(XVIII)]3 ? Linker GAG Basal lamina Not known
Transmembrane
XIII [1(XIII)]3 Transmembrane Integrin 11, Not known
fibronectin
XVII [1(XVII)]3 Transmembrane Basal lamina Hemidesmosomes, Blistering conditions; antigen in
epidermaldermal bullous pemphigoid
junction
522 SECTION VIII n Cellular Adhesion and the Extracellular Matrix

APPENDIX 29.2

Proteoglycans
Name Core Protein Glycosaminoglycans Expression Functions
Secreted Proteoglycans
Aggrecan One-gene, 250-kD protein with 100150 keratin sulfate Cartilage Binds hyaluronan and link
link protein, EGF, lectin & chains >150 protein; hydrates and fills
complement regulatory chondroitin sulfate the ECM; no known diseases
domains chains
Biglycan One-gene, 38-kD protein 2 Chondroitin sulfate or Developing muscle, Associated with cell surfaces;
dermatan sulfate bone, cartilage, and no known ligands or
chains epithelia functions
Decorin One-gene, 38-kD protein 1 Chondroitin sulfate or Connective tissue Binds collagen fibrils and
dermatan sulfate chain fibroblasts modifies their assembly
Fibromodulin One-gene, 43-kD protein 4 Asparagine-linked Cartilage, skin, tendon Binds collagen I and II; limits
keratin sulfate chains size of collagen fibrils
Perlecan One-gene, 400-kD protein 3 Heparan sulfate All cells making Self-associates; binds laminin
chains of 3060kD basement membranes in basal lamina; binds basic
(epithelia, muscle, fibroblast growth factor
peripheral nerve)
Serglycin One-gene, 12-kD protein; 24 Heparin or chondroitin White blood cells, mast Binds histamine in secretory
serine-glycine repeats sulfate cells granules
Versican One-gene, 260-kD protein with 1215 chondroitin Fibroblasts; ? other May bind hyaluronan;
link-protein, GAG attachment, sulfate chains N- cells functions unknown
2 EGF, lectin & complement and O-linked
regulatory domains oligosaccharides
Membrane-Associated Proteoglycans
Fibroglycan One-gene, integral membrane Heparan sulfate chains Fibroblasts Binds collagen I and
protein of 20kD fibronectin; cell adhesion to
ECM
Glypican 62-kD protein with 4 Heparan sulfate Lung, skin, epithelia, Binds fibronectin, collagen I,
glycosylphosphatidylinositol chains endothelium, smooth and antithrombin III; cell
anchor to membrane on muscle adhesion to ECM
C-terminus
Syndecan One-gene, integral membrane Variable number of Embryonic epithelia Binds fibronectin; collagens I,
protein of 33kD heparan sulfate and and mesenchyme, III, and V; thrombospondin;
chondroitin sulfate developmentally basic fibroblast growth
chains regulated in adult factor; cell adhesion to ECM
lymphocytes

ECM, extracellular matrix; EGF, epidermal growth factor; GAG, glycosaminoglycan.

 CHAPTER 29 n Extracellular Matrix Molecules 523

APPENDIX 29.3

Adhesive Glycoproteins
Name(s) Composition Expression Ligands Functions and Diseases
Agrin One-gene, 205-kD protein Motor neurons secrete ? Acetylcholine Aggregates acetylcholine
with cysteine-rich, EGF, into basal lamina of receptor receptors
and Kazal protease neuromuscular
inhibitor domains junction
Fibrinogen 2 67kD A chains, Hepatocytes secrete into Platelet integrin Thrombin cleavage releases
2 56kD B chains, blood GPIIb/GPIIIa fibrin, which polymerizes
2 47kD chains, into fibrils stabilized by
joined by disulfide bonds; covalent crosslinking by
N-linked CHO on B & transglutaminase;
chains deficiency or defects
cause bleeding
Fibronectin One gene; RNA splicing Many tissues; increased Fibrin, heparin, Assembles fibrils in ECM;
isoforms of 235270kD; with wounding cells via integrins, promotes cellular
dimers disulfide-bonded; collagen adhesion to ECM and
12 FN-I, 2 FN-II and migration
1517 FN-III domains;
N- and O-linked CHO
Fibulin One gene; RNA splicing Fibroblasts; present in Ca2+, fibronectin, Required for elastin
generates monomeric plasma and some fibrinogen assembly; mutated in
isoforms of 566, 601 and basement membranes some patients with
683 residues with 9 EGF macular degeneration
and 3 complement-like
domains; N- and O-linked
CHO
HB-GAM (heparin- 136 residues, 5 internal Brain, uterus, intestine, Heparin ? Neuronal differentiation
binding, growth- disulfide bonds kidney, muscle, lung,
associated molecule) skin
Laminin 1 200400kD A chain, Epithelium, endothelium, Nidogen, 6 integrins Self-associates into network
1 200kD B1 chain, smooth & striated perlecan, collagen in basement membrane
1 200kD B2 chain, muscle, peripheral IV, -dystroglycan linked to collagen IV
several isoforms of nerve, myotendinous network by nidogen;
each; poly-N-acetyl junction promotes cell adhesion
galactosamine and migration
Laminin-binding Soluble S-type monomeric Macrophages, epithelia, Poly-N-acetyl ?
protein (Mac-2) lectin of 2935kD fibroblast, trophoblast, galactosamine on
cancer cells laminin
Link protein One gene; alternative Cartilage Aggrecan and Links aggrecan to
splicing generates hyaluronan hyaluronan
isoforms of 41, 46, &
51kD with two
4-cysteine & one
immunoglobulin domains;
CHO content variable
Mucins Heterogeneous secreted & GI tract, salivary glands Selectins Lubricates mucous
transmembrane membranes
glycoproteins
Nidogen (entactin) One-gene, 148-kD Basement membranes of Laminin, collagen Links collagen IV to laminin
monomeric protein with epithelia, muscles, and IV, Ca2+ in basement membrane
8 EGF & 2 EF hand nerves
domains; N- & O-linked
CHO
Osteopontin (secreted Monomer of ~300 residues, Bone, milk, kidney, ? Vitronectin Promotes cell adhesion to
phosphoprotein) phosphorylated, N- & uterus, ovary receptor; ? ECM, including
O-linked CHO, including hydroxyapatite osteoclasts to bone
sialic acid
Continued
524 SECTION VIII n Cellular Adhesion and the Extracellular Matrix
APPENDIX 29.3
Adhesive Glycoproteinscontd
Name(s) Composition
Restrictin 3 180kD chains linked
by disulfide bonds; each
has 1 cysteine-rich, EGF,
9 FN-III and 1 fibrinogen-
like domains
SPARC (secreted One-gene; 32-kD monomer
protein rich in
cysteine);
osteonectin
Tenascin (cytotactin) Four genes (C, R, X, Y) and
alternate splicing; EGF,
FN-III, and fibrinogen-like
domains; chains linked by
disulfides
Thrombospondin 420-kD protein with
procollagen, EGF, and
complement-like domains
Vitronectin One-gene, 75-kD protein
with N-linked CHO,
phosphorylated, sulfated
Secreted by liver into
blood
von Willebrand factor One-gene, 2050-residue
protein that forms head
to head and tail to tail
disulfide-linked oligomers,
N- & O-linked CHO
CHO, oligosaccharide chains; ECM, extracellular matrix; EF hand, calcium binding motif of calmodulin family; EGF, epidermal growth factor;
GPI, glycosylphosphatidylinositol; FN, fibronectin; Ig-CAM, immunoglobulin cell adhesion molecule.
Expression Ligands Functions and Diseases
A limited number of Cells, receptor ? Cell adhesion
neurons in embryonic unknown
nervous systems
Bone, skin, connective Collagens III and ? Wound healing,
tissue V, Ca2+, development
hydroxyapatite,
cells
Embryonic mesenchyme; Integrins, Ig-CAMs, Tenascin-X mutated in
adult perichondrium, proteoglycans some patients with
periosteum, tendon, Ehlers-Danlos syndrome;
ligament, myotendinous mice with tenascin-C null
junction, wounds mutation develop
normally
Platelets, fibroblasts, Integrin v3, CD36 Platelet aggregation;
embryonic heart, cell surface stimulates proliferation of
muscle, bone, brain receptor, smooth muscle; inhibits
syndecan, Ca2+ proliferation of
endothelium
Integrin V3, heparin, Promotes cell
glass, plastic adhesion,
inactivates
heparin, stabilizes
plasminogen
activator inhibitor
Endothelium, platelets Factor VIII, heparin, Promotes adhesion of
collagen, platelet platelets to collagen
integrin GPIIb/ and each other; required
GPIIIa to control bleeding;
deficiency causes most
common congenital blood
clotting abnormality