TITLE: THE PRIMARY STRUCTURE OF PROTEIN DETERMINES THE QUATENARY STRUCTURE OF A PROTEIN AND CERTAIN FUNCTIONAL PROPERTIES OF A PROTEIN.

NAME: OMONIYI AKINTUNDE TEMILOLUWA LEVEL: 200 DEPARTMAENT: MEDICINE AND SURGERY SESSION: 2011/2012 A FORMATIVE TEST SUBMITTED TO THE DEPARTMENT OF BIOCHEMISTRY IN PARTIAL FUFILLMENT OF THE REQUIREMENT TO SIT AND ENTER FOR THE PART 1 MBBS EXAMINATION

roteins are a diverse and abundant class of biomolecules, constituting more than

50% of the dry weight of cells. This diversity and abundance reflect the central role of proteins in virtually all aspects of cell structure and function. An extraordinary diversity of cellular activity is possible only because of the versatility inherent in proteins, each of which is specifically tailored to its biological role. The pattern by which each is tailored resides within the genetic information of cells, encoded in a specific sequence of nucleotide bases in DNA. Each such segment of encoded information defines a gene, and expression of the gene leads to synthesis of the specific protein encoded by it, endowing the cell with the functions unique to that particular protein. Proteins are the agents of biological function; they are also the expressions of genetic information. Chemically, proteins are unbranched polymers of amino acids linked head to tail, from carboxyl group to amino group, through formation of covalent peptide bonds, a type of amide linkage (Figure 5.1).

Peptide bond formation results in the release of H2O. The peptide backbone of a protein consists of the repeated sequence -N-C-C-, where the N represents the amide nitrogen, the C is the -carbon atom of an amino acid in the polymer chain, and the final C is the carbonyl carbon of the amino acid, which in turn is linked to the amide N of the next amino acid down the line. The geometry of the peptide backbone is shown in Figure 5.2. Note that the carbonyl oxygen and the amide hydrogen are trans to each other in this figure. This conformation is favored energetically because it results in less steric hindrance between nonbonded atoms in neighboring amino acids. Because the -carbon atom of the amino acid is a chiral center (in all amino acids except glycine), the polypeptide chain is inherently asymmetric. Only L-amino acids are found in proteins. Peptide Classification Peptide is the name assigned to short polymers of amino acids. Peptides are classified by the number of amino acid units in the chain. Each unit is called an amino acid residue, the word residue denoting what is left after the release of H2O when an amino acid forms a peptide link upon joining the peptide chain. Dipeptides have two amino acid residues, tripeptides have three, tetrapeptides four, and so on. After
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about 12 residues, this terminology becomes cumbersome, so peptide chains of more than 12 and less than about 20 amino acid residues are usually referred to as oligopeptides, and, when the chain exceeds several dozen amino acids in length, the term polypeptide is used. The distinctions in this terminology are not precise. Proteins Are Composed of One or More Polypeptide Chains The terms polypeptide and protein are used interchangeably in discussing single polypeptide chains. The term protein broadly defines molecules composed of one or more polypeptide chains. Proteins having only one polypeptide chain are monomeric proteins. Proteins composed of more than one polypeptide chain are multimeric proteins. Multimeric proteins may contain only one kind of polypeptide, in which case they are homomultimeric, or they may be composed of several different kinds of polypeptide chains, in which instance they are heteromultimeric. Greek letters and subscripts are used to denote the polypeptide composition of multimeric proteins. Thus, an 2-type protein is a dimer of identical polypeptide subunits, or a homodimer. Hemoglobin (Table 5.1) consists of four polypeptides of two different kinds; it is an 2 2 heteromultimer.

Architecture of Protein Molecules

Protein Shape As a first approximation, proteins can be assigned to one of three global classes on the basis of shape and solubility: fibrous, globular, or membrane (Figure 5.7). Fibrous proteins tend to have relatively simple, regular linear structures. These proteins often serve structural roles in cells. Typically, they are insoluble in water or in dilute salt soluble. In contrast, globular proteins are roughly spherical in shape. The polypeptide chain is compactly folded so that hydrophobic amino acid side chains are in the interior of the molecule and the hydrophilic side chains are on the outside exposed to the solvent, water. Consequently, globular proteins are usually very soluble in aqueous
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solutions. Most soluble proteins of the cell, such as the cytosolic enzymes, are globular in shape. Membrane proteins are found in association with the various membrane systems of cells. For interaction with the nonpolar phase within membranes, membrane proteins have hydrophobic amino acid side chains oriented outward. As such, membrane proteins are insoluble in aqueous solutions but can be solubilized in solutions of detergents. Membrane proteins characteristically have fewer hydrophilic amino acids than cytosolic protein.
.LEVEL OF PROTEIN STRUCTURE

Protein structure, from primary to quaternary structure. There are four distinct levels of protein structure.

Primary structure
Main article: Protein primary structure The primary structure refers to amino acid sequence of the polypeptide chain. The primary structure is held together by covalent or peptide bonds, which are made during the process of protein biosynthesis or translation. The two ends of the polypeptide chain are referred to as the carboxyl terminus (C-terminus) and the amino terminus (N-terminus) based on the nature of the free group on each extremity. Counting of residues always starts at the N-terminal end (NH2group), which is the end where the amino group is not involved in a peptide bond. The primary structure of a protein is determined by the gene corresponding to the protein. A specific sequence of nucleotides in DNA is transcribed into mRNA, which is read by the ribosome in a process called translation. The sequence of a protein is unique to that protein, and defines the structure and function of the protein. The sequence of a protein can be determined by methods such as Edman degradation or tandem mass spectrometry. Often however, it is read directly from the sequence of the gene using the genetic code. Post-translational modifications such as disulfide formation, phosphorylations and glycosylations are usually also considered a part of the primary structure, and cannot be read from the gene. AMINO ACID RESIDUE Each -amino acid consists of a backbone part that is present in all the amino acid types, and a side chain that is unique to each type of residue. An exception from this rule is proline. Because the carbon atom is bound to four different groups it is chiral, however only one of the isomers occur in biological proteins. Glycine however, is not chiral since its side chain is a hydrogen atom. A simple mnemonic for correct L-form is "CORN": when the C atom is viewed with the H in front, the residues read "CO-R-N" in a clockwise direction

Secondary structure

An alpha-helix with hydrogen bonds (yellow ) Secondary structure refers to highly regular local sub-structures. Two main types of secondary structure, the alpha helix and the beta strand or beta sheets, were suggested in 1951 by Linus Pauling and coworkers.[2] These secondary structures are defined by patterns of hydrogen bonds between the main-chain peptide groups. They have a regular geometry, being constrained to specific values of the dihedral angles and on the Ramachandran plot. Both the alpha helix and the beta-sheet represent a way of saturating all the hydrogen bond donors and acceptors in the peptide backbone. Some parts of the protein are ordered but do not form any regular structures. They should not be confused with random coil, an unfolded polypeptide chain lacking any fixed three-dimensional structure. Several sequential secondary structures may form a "supersecondary unit".[3]

Tertiary structure
Main article: Protein tertiary structure Tertiary structure refers to three-dimensional structure of a single protein molecule. The alphahelices and beta-sheets are folded into a compact globule. The folding is driven by the nonspecific hydrophobic interactions (the burial of hydrophobic residues from water), but the structure is stable only when the parts of a protein domain are locked into place by specific tertiary interactions, such as salt bridges, hydrogen bonds, and the tight packing of side chains and disulfide bonds. The disulfide bonds are extremely rare in cytosolic proteins, since the cytosol is generally a reducing environment.

Quaternary structure
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Main article: Protein quaternary structure

Quaternary structure is a larger assembly of several protein molecules or polypeptide chains, usually called subunits in this context. The quaternary structure is stabilized by the same non-covalent interactions and disulfide bonds as the tertiary structure. Complexes of two or more polypeptides (i.e. multiple subunits) are called multimers. Specifically it would be called a dimer if it contains two subunits, a trimer if it contains three subunits, and a tetramer if it contains four subunits. The subunits are frequently related to one another by symmetry operations, such as a 2-fold axis in a dimer. Multimers made up of identical subunits are referred to with a prefix of "homo-" (e.g. a homotetramer) and those made up of different subunits are referred to with a prefix of "hetero-" (e.g. a heterotetramer, such as the two alpha and two beta chains of hemoglobin. A. Primary Structure Determines Folding

the primary structure of a protein determines its three-dimensional conformation. more specifically, the sequence of amino acid side chains dictates the fold pattern of the three-dimensional structure and the assembly of subunits into quaternary structure. under certain conditions, denatured proteins can refold into their native conformation, regaining their original function. proteins can be denatured with organic solvents such as urea that disrupt hydrophobic interactions and convert the protein to a soluble random coil. many simple single-subunit proteins like ribonuclease that are denatured in this way spontaneously refold into their native conformation if carefully brought back to physiologic conditions. even complex multi-subunit proteins containing bound cofactors can sometimes spontaneously renature under the right conditions. thus, the primary structure essentially specifies the folding pattern. in the cell, not all proteins fold into their native conformation on their own. as the protein folds and refolds while it is searching for its native low energy state, it passes through many high-energy conformations that slow the process (called kinetic barriers). these kinetic barriers can be overcome by heat shock proteins, which use energy provided by atp hydrolysis to assist in the folding process . Heat shock proteins were named for the fact that their synthesis in bacteria increased when the temperature was suddenly raised. they are present in human cells as different families of proteins with different activities. for example, the hsp70 proteins bind to nascent polypeptide chains as their synthesis is being completed to keep the uncompleted chains from folding prematurely. they also unfold proteins prior to their insertion through the membrane of mitochondria and other organelles. the multi-subunit barrel-shaped hsp60 family of proteins is called chaperonins. the unfolded protein fits into the barrel cavity that excludes water and serves as a template for the folding process. the hydrolysis of several atp molecules is used to overcome the energy barriers to reaching the native conformation. a cis-trans isomerase and a disulfide isomerase also participate in folding. the cis-trans isomerase converts a trans peptide bond preceding a proline into the cis conformation, which is well suited for making hairpin turns. the disulfide isomerase breaks and reforms disulfide bonds between the -sh groups of two cysteine residues in transient structures formed during the folding process. after the protein has folded, cysteine-sh groups in close contact in the tertiary structure can react to form the final disulfide bonds.
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SICKLE CELL DISEASE: A CHANGE IN PRIMARY STRUCTURE Even a slight change in primary structure can affect a proteins shape and ability to function. For instance, sickle cell disease and inherited blood disorder, is caused by substitution of one amino acid (glutamine)with another amino acid (valine) at a particular position in the globin structure of haemoglobin. This simple substitution cause a distortion in the shape of the red blood cell. This condition shows us how a simple change in protein structure can lead in the change of the whole structure. REFERENCE MARKS BASIC MEDICAL BIOCHEMISTRY 2ND EDITION COLLEN M. SMITH PHD ALLAN D. MARKS MD MICHEAL A. LIBERMANN PHD WIKIPEDIA FREE SEARCH ENGINE BIOCHEMISTRY FIFTH EDITION JEREMY M. BERG JOHA L.TYMOCAKO.