Peptide and Protein

Structure and Function

Harliansyah, Ph.D
Dept. Biochemistry School of Medicine
University of YARSI
2013

From amino acids to protein:

N-terminus
terminates
by an amino group
Peptide bond

Amino acid

C-terminus
terminates by a
carboxyl group
A peptide: Phe-Ser-Glu-Lys (F-S-E-K)

Formation of a peptide bond:

Dipeptide = 2 A.A
Tripeptide = 3 A.A
Oligopeptide = <20 A.A
Polypeptide = > 20 A.A.
Proteins >50 amino acids
Amino acid with free a-amino group is the aminoterminal or N-terminal residue
Amino acid with free a-carboxyl group is the
carboxyl-terminal or C-terminal residue
Three letter code Met-Gly-Glu-Thr-Arg-His
Single letter code M-G-E-T-R-H
Each amino acid residue is called by replacing
-ine or -ate with yl = carboxyl - hydroxyl (acyl)
glycine glycyl
glutamate glutamyl
asparagine, glutamine, cysteine asparaginyl,
glutaminyl, cysteinyl.

Naming of Peptides
For naming peptides, the AA suffixes ine

(glycine), - an (tryptophan) ate (glutamate)

are changed to yl with the exception of C
terminal AA.

A tripeptide composed of an N terminal

glutamate, a cysteine and a C terminal
glycine is called:
glutamyl cysteinyl - glycine

Characteristics of Peptide
Bonds
Rigid
Planar
Partial double bond in character
Generally exists in transconfiguration
Both _C = O and _NH2 groups of peptide
bonds are polar
6. Involved in hydrogen bond formation
1.
2.
3.
4.
5.

Peptides of Physiologic
Importance
1. Glutamine

- a tripeptide composed of 3 AA
- gamma glutamyl cysteinyl glycine
- wildly distributed in nature
- exists in reduced or oxidized states

Functions:
a) As a coenzyme for certain enzymes as
prostaglandin PGE2
synthase
glycoxylase
b) Prevents the oxidation of sulfhydryl groups of
several proteins to disulfide groups
c) In association with glutathione reductase
participates in the formation of correct disulfide
bonds in several protiens
d) In erythrocytes
- maintains RBC membrane structure and
integrity
- protects hemoglobin from getting oxidized by
agents such as H2O2

e) Involved in the transport of AA

in the intestine and kidney
tubules via delta glutamyl cycle
or Meister cycle
f) Involved in the detoxification
process
g) Toxic amounts of peroxidases
and free radicals produced in the
cells are scavanged by
glutathione peroxidase ( a

2. Thyrotropin Releasing Hormone (TRH)

- a tripeptide secreted by hypothalamus
Function:
Stimulates pituitary gland to release
thyrotropic hormone
3. Oxytocin
- contains 9 AA (nonapeptide)
- hormone secreted by posterior
pituitary gland
Function:
Causes contraction of the uterus

4. Vasopressin (ADH antidiuretic hormone)

- also a nonapeptide
- produced by posterior pituitary gland
Function:
Stimulates kidneys to retain water and
thus increases the blood pressure
5. Angiotensins
- Angiotensin 1 a decapeptide (10AA)
which is converted to angiotensin II (8AA)
Function:
For the release of aldosterone from
adrenal gland

6. Methionine Enkephalin
- a pentapeptide found in the brain and
has opiate like function.
Function:
It inhibits the sense of a pain.
7. Bradykinin and Kallidin
- nona and decapeptides respectively
- produced from plasma proteins by
snake venom enzymes
Function:
Powerful vasodilators

8. Peptide Antibiotics
- Antibiotics such as Gramicidin,
Bacitracin, tyrocidin and Actinomysin
peptide in nature
9. Substance P
- a decapeptide
- acts as neurotransmitter
10. Gastrointestinal Hormones
- Gastrin, Secretin & etc.
- gastrointestinal peptides serving as
hormones

Four Levels of Structure Determine the

Shape of Proteins
Primary structure
The linear arrangement (sequence) of amino acids and the location of covalent (mostly
disulfide) bonds within a polypeptide chain. Determined by the genetic code.

Secondary structure

local folding of a polypeptide chain into regular structures including the helix,
sheet, and U-shaped turns and loops.

Tertiary structure
overall three-dimensional form of a polypeptide chain, which is stabilized by multiple
non-covalent interactions between side chains.

Quaternary structure:
The number and relative positions of the polypeptide chains in multisubunit
proteins. Not all protein have a quaternary structure.

Primary Structure

Pro-insulin is
produced in the
Pancreatic islet
cells

C-peptide

Pro-insulin protein

65/66

30/31

Human:
Thr-Ser-Ile
Cow:
Ala-Ser-Val
Pig:
Thr-Ser-Ile
Chiken:

His-Asn-Thr
Insuline
C-peptide
+ C peptide

Aminoacidsubstitutioninproteinsfromdifferentspecies
Conservative

Substitutionofanaminoacidbyanother
aminoacidofsimilarpolarity
(ValforIleinposition10ofinsulin)

Nonconservative

Substitutioninvolvingreplacement
ofanaminoacidbyanotherof
differentpolarity

(sicklecellanemia,6thpositionofhemoglobin
replacefromaglutamicacidtoavalineinduce
precipitationofhemoglobininredbloodcells)

Invariantresidues

Aminoacidfoundatthesamepositionin
differentspecies
(criticalforforthesructureorfunctionoftheprotein)

Stabilized by hydrogen bonds

H- bonds are between CO and NH
groups of peptide backbone
H-bonds are either intra- or intermolecular
3 types : a-helix, b-sheet and triple-helix

eet:

from hydrogen bonding, does not involve the side chain of the amino ac

The helix:

result from hydrogen bonding, does not involve the side chain
of the amino acid

TERTIARY
STRUCTURE
R-group interactions result in 3D structures of

globular proteins
Types of interactions : H-, ionic- (salt linkage),
hydrophobic- and disulphide- bond
Hydrophilic R groups on surface while
hydrophobic R groups buried inside of molecule
Wide variety of 3o structures: since large
variation in protein sizes and amino acid
sequences

Theroleofsidechaininthe Whereiswater?
shapeofproteins
Hydrophilic

Hydrophobic

Quaterner
y
structure:
If protein is formed as a
complex of more than
one protein chain, the
complete structure is
as quaternery
designed
Generally formed by
structure:
non-covalent
interactions between
subunits
Either as homo- or
hetero-multimers

Protein domains:
Any part of a protein that can fold
independently into a compact,
stable structure. A domain usually
contains between 40 and 350
amino acids.

A domain is the modular unit

from which many larger proteins
are constructed.
The different domain of protein

Protein
domains

The NADbinding
Cytochrome b562
domain of
A single domain protein
nvolved in electron transport the enzyme
lactic
n mitochondria
dehydrogenas
e

The variable
domain of an
immunoglobulin

Classes of protein
1Structuralprotein:Keratin,Collagen(givesupporttocells)
2Dynamicprotein:Hormone,enzyme(forcatalyticpurpose)
Basedonthestructure,proteincanbedividedto:
*Fibrin:Bloodclotting
*Fibrous:Myosin(frommuscle)
*Globular:Halfsphereform/structureeg.Enzyme
Size:Varieddependingonfunctions
1aminoacid=110Daltons
Mostproteinarehighlyfolded

FibrousandGlobularProteins

 4 different forces stabilize the tertiary structure of globular

protein
i. Hydrogen bonding between R groups of residues in
adjacentloopsofthechain
ii.IonicattractionbetweenoppositelychargedRgroups
iii.Hydrophobicinteractions
iv.Covalentcrosslinkages(viaintrachaincysteinresidues)

Function of proteins
Enzymatic catalysis
Transport and storage (the protein hemoglobin,
albumins)
Coordinated motion (actin and myosin).
Mechanical support (collagen).

Proteins
are the most
important buffers in
the body.

Immune protection (antibodies)

Generation and transmission of nerve impulses
- some amino acids act as neurotransmitters,
receptors for neurotransmitters, drugs, etc. are
protein in nature. (the acetylcholine receptor),
Control of growth and differentiation transcription factors
Hormones
growth factors ( insulin or thyroid stimulating
hormone)

Why?
(a) Protein molecules
possess basic and
acidic groups which
act as H+ acceptors
or donors
respectively if H+ is
added or removed.

(a) Proteins are the most important buffers in the body. They are
mainly intracellular and include haemoglobin.
(b) The plasma proteins are buffers but the absolute amount is
small compared to intracellular protein.
(c) Protein molecules possess basic and acidic groups which act as
H+ acceptors or donors respectively if H+ is added or removed.

Many proteins (thousands!) present in blood plasma

Proteins contain weakly acidic (glutamate, aspartate) and basic
(lysine, arginine, histidine) side chains (or R groups)
At neutral pH, only histidine residues (containing imidazole R group
with pKa ~ 6.0) in proteins can act as a buffer component
Haemoglobin with 38 histidine/tetramer is a good buffer
N-terminal groups of proteins (pKa ~ 8.0) can also act as a buffer
component

Proteins play crucial roles in almost every biological process.

They are responsible in one form or another for a variety of
physiological functions including

Enzymatic catalysis
Transport and storage
Coordinated motion
Mechanical support
Immune protection
Generation and transmission of nerve impulses
Control of growth and differentiation

Enzyme Catalysis

Transport and storage - small molecules are often carried by proteins in the
physiological setting (for example, the protein hemoglobin is responsible for the transport of
oxygen to tissues). Many drug molecules are partially bound to serum albumins in the plasma.

The binding of oxygen is affected by molecules such as

carbon monoxide (CO) (for example from tobacco smoking,
cars and furnaces).
CO competes with oxygen at the heme binding site.
Hemoglobin binding affinity for CO is 200 times greater than
its affinity for oxygen, meaning that small amounts of CO
dramatically reduces hemoglobin's ability to transport
oxygen. When hemoglobin combines with CO, it forms a
very bright red compound called carboxyhemoglobin.

3-dimensional structure of
hemoglobin. The four subunits are
shown in red and yellow, and the
heme groups in green.

When inspired air contains CO levels as low as 0.02%,

headache and nausea occur; if the CO concentration is
increased to 0.1%, unconsciousness will follow. In heavy
smokers, up to 20% of the oxygen-active sites can be
blocked by CO.

Coordinated motion - muscle is mostly protein, and muscle contraction is mediated by

the sliding motion of two protein filaments, actin and myosin.

Platelet activation is a
controlled sequence of actin
filament:
Severing
Uncapping
Elongating
Cross linking
That creates a dramatic shape
change in the platelet

Platelet before activation

Activated platelet

Activated platelet
at a later stage than C)

Mechanical support - skin and bone are strengthened by the protein collagen.

Abnormal collagen
synthesis or structure
causes dysfunction of

cardiovascular organs,
bone,
skin,
joints
eyes

Refer to Devlin
Clinical correlation 3.4 p121

Immune protection - antibodies are protein structures that are responsible for
reacting with specific foreign substances in the body.

Generation and transmission of nerve impulses Some amino acids act as neurotransmitters, which transmit electrical signals from one nerve cell to
another. In addition, receptors for neurotransmitters, drugs, etc. are protein in nature.
An example of this is the acetylcholine receptor, which is a protein structure that is embedded in
postsynaptic neurons.

GABA:
gamma Amino butyric acid
Synthesised from glutamate
GABA acts at inhibitory synapses in
the brain. GABA acts by binding to
specific receptors in the plasma
membrane of both pre- and
postsynaptic neurons.
Neurotransmetter

Control of growth and differentiation proteins can be critical to the control of growth, cell differentiation and expression of DNA.
For example, repressor proteins may bind to specific segments of DNA, preventing expression and
thus the formation of the product of that DNA segment.
Also, many hormones and growth factors that regulate cell function, such as insulin or thyroid
stimulating hormone are proteins.

Insuline

Membrane transport proteins

Shape and function

Disease and protein folding:

Disease
Exemple:
Neurodegenerative
diseases

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