2006-Protein Structure and Function

7/27/2019 2006-Protein Structure and Function

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Amino Acid and Protein 1

Proteins Structure andFunction

SPECIFIC LEARNING OBJECTIVE

At the end of the session the student should be able to

explain:

Structures of amino acids

Peptides and proteinsClassification of protein

Denaturation of protein

Prion protein


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I .AMINO ACIDAmino acids are fundamental units of proteins.


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continued


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Structure of the -Amino Acids

All proteins are polymers, and the monomerscombine are -Amino Acids.

A representative -Amino Acids, e.g.. valineis shown in figure:


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7/58Amino Acid and Protein 7

A. Composition

The amino group are attached to the -carbon,the carbon next to the carboxyl group, hencethe name -amino acids.

To the -carbon of every amino acid are alsoattached a hydrogen atom and side chains (R).

Their different side chains distinguish different-amino acids.

We can write the general structure for an -amino acid in next figure:



The complete structures of these amino acidsare shown in next slide (slide no.9).

Only 20 -amino acids used by cells when they

synthesize protein. Hydroxyproline, present mainly in collagen, is

synthesized from proline, and cystine, present inmost proteins, is synthesized from cysteine.



B. Amphoteric properties Amino acids are amphoteric molecules ; that is,

they have both basic and acidic groups

Monoamino-monocarboxylic acids exist in solutionneutral pH are predominantly dipolar ions (orzwitter ion). In dipolar form of an amino acid, theamino group is protonated and positively charged(-NH3

+) and the carboxyl group is dissociated andnegatively charged (-COO-)

At low pH, the carboxyl group accepts a protonand becomes uncharged, so that the overallcharge on the molecule is positive

At high pH, the amino group loses its proton andbecomes uncharged; thus, the overall charge onthe molecule is negative



C. Stereochemistry of the -amino acids

The -carbon of amino acids are formed anasymmetric molecule, the -carbon is said tobe chiral or stereocenter or also called anasymmetric carbon.

The important fact that all of the amino acidsincorporated by organisms into proteins areof the L-form, with the exception ofglycine

D-isomers of amino acids exist in nature, andsome play important biochemical roles butthey are never found in proteins.



D. Properties of amino acid side chains

Some amino acids have side chains that

contain dissociating groups. Side chains: aspartate and glutamate are

acidic: Histidine, lysine and arginine are basic

Side chains : cystein and tyrosine, have a

negative charge on the side chain whendissociated

Dissociating groups. For example, glutamatehas three dissociable protons with pKa 2.1,

3.9.and 9.8. As the pH increases above each ofthese pKa values, proton dissociate and thecharge changes as shown: overall charge 1+,0, +1 and 2+ respectively



E. Classes of -amino acids.

1. Amino Acids with Aliphatic Side Chain

Glycine, alanine, valine, leucine, andisoleucine have aliphatic, or alkane, side chain.

The R group becomes more extended and morehydrophobic.

Isoleucine, for example the more hydrophobicamino acidsare usually found within a proteinmolecule, where they are shielded from water.

Proline, note that proline is cyclic amino acids

although it is cyclic amino acid; its side chain has aprimarily aliphatic character. However the rigidity ofthe ring often makes the folding proline residuesinto protein structure difficult.



2. Amino acids with Hydroxyl or Sulfur-Containing Side Chains

In this category are serine, cysteine, threonine,and methionine, because of their weakly polar sidechains, are generally more hydrophilic thanaliphatic chains,

Although methionine is fairly hydrophobic.



Cystein.

First, the side chain can ionize atmoderately high pH;



Second, oxidation can occur between pairs ofcysteine side chains to form a disulfide bond. Theproduct of this oxidation is given the name cystine.

The presence of such disulfide bonds betweencysteine residues in proteins often plays animportant structural role



The primary structure of bovine insulin



3. Aromatic Amino Acids Three amino acids, phenylalanine, tyrosine,

tryptophan, carry aromatic side chains

Phenylalanine, together with the aliphaticamino acids valine, leucine and isoleusine, isone of the hydrophobic amino acids.

Tyrosine and tryptophan have somehydrophobic character as well.


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4. Basic Amino Acids

Histidine, lysine, and arginine carry basicgroups in their side chains. They arerepresented in Figure 5.3 in the form thatexists at pH values near neutrality.

Histidine is the least basic of the three. Lysine and arginine are more basic amino

acids, their side chains are always positivelycharged

The basic amino acids are strongly polar, theyare usually found on the exterior surfaces ofproteins (hydrophilic), where the surroundingaqueous environment can hydrate them.


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5. Acidic Amino Acids and Their Amides

Aspartic acids and glutamic acid are the onlyamino acids that carry negative charges at pH7: they are represented in the anionic forms inFigure 5.3.

Companion to aspartic acid and glutamic acidsare their amides, asparagines and glutamine.

Asparagine and glutamine have uncharged sidechains, although they are decidedly polar. Like

the basic and acidic amino acids, they aredefinitelyhydrophilic and tend to be on thesurface of a protein molecule, in contact withsurrounding water.


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MODIFIED AMINO ACIDS

Representation of several such modified amino

acids follows, with the modifying group shown inred : Figure phosphoserine, 4-hydroxyproline, hydroxylysine - Carboxyglutamic acid

Phosphoserine, source many protein e.g enzymes

etc 4-hydroxyproline, source collagen and gelatine

hydroxylysine, source collagen and gelatine

- Carboxyglutamic acid, source Prothrombin

and bone protein And many other amino acids play important roles

in metabolism is given in Table 5.2.


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continued


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PEPTIDES AND THE PEPTIDE BOND

Amino acids can be covalently linked togetherby formation of an amide bond between the -carboxyl group of one amino acid and the -amino group on another.

This bond is referred to as peptide bond,and the products formed are called peptides.The peptide bond is nearly planar, and thetrans form is favored. The process is highly

endergonic (i.e. energy-requiring) and requiresthe concomitant hydrolysis of high-energyphosphate bonds


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The formation of a peptide bond betweenglycine and alanine is shown in Figure 5.8. The

product is called dipeptide, the reaction canbe eliminated a water molecule. Chainscontaining four amino acid residues are referredtetrapeptide shown in Figure 5.9.

E G A K


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The portion of each amino acids remaining inthe chain is called an amino acid residue

Chains containing a few amino acid residuesare collectively referred to as oligopeptides.

If the chain is very long, it is called apolypeptide. Oligopeptides and polypeptides

are formed by polymerization of amino acidsvia peptide bonds

In writing the sequence of an oligopeptide orpolypeptide that the convention is to alwayswrite the N-terminal amino acid (the residuehas a free -amino group) to the left, and theC-terminal to the right. (the residue has a free-carboxyl group)


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Large peptide chain. Protein polypeptidechain are typically more than 100 amino acidresidue. All proteins are polypeptides. This iswhy understanding the nature of polypeptides

and the peptide bond is so important a part ofbiochemistry.

Small peptide chainsare common and oftenhave important biologic roles. For example thehormone glucagon has 29 residues,vasopressin has 9 residue and thyrotropin-releasing hormone has 3 residue


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CONFORMATION OF PROTEINS

Every protein in its native state has aunique three-dimentional structure, whichreferred to as its conformation.

The function of a protein arises from itsconformation.

Protein structures can be classified intofour levels of organization : primary,secondary, tertiary, and quartenary.


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The primary structure is the covalentbackbone of the polypeptide formedby the specific sequence. This sequenceis coded for by DNA and determinesthe final three dimensional fromadopted by the protein in its nativestate


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The secondary structureis the spatial

relationships of neighboring amino acid residue.1. Secondary structure is dictated by

primary structure. The secondary structurearises from interactions of neighboring amino

acids. Because DNAcoded primary sequencedictated which amino acids are near eachother, secondary structure often form as thepeptide chain comes off the ribosome.


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2. Hydrogen bonds, these formation very

important characteristic of secondarystructure, (H-bond) between the CO- groupof one peptide bond and theNH group ofanother nearby peptide bond.

(a). If the H-bonds form between peptide bonds inthe same chain, either helical structure such asthe -helix develop or turn such as -turns areformed.

(b). If the H-bonds form between peptide bonds indifferent chains, extended structures form, suchas the -pleated sheet.


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3. The-helixis rod like structure with thepeptide bond coiled tightly inside and the side

chain of the residue protruding outward.(a). Characteristics

(1.) EachCO is hydrogen-bonded to theNH ofa peptide bond that is four residues away

from it along the same chain2.) There are 3.6 amino acid residue per turn of

the helix, and the helix is right-handed (turnin a clockwise around the axis)

(b). Helical structures in proteins were predictedby Linus Pauling from his studies of fibrous proteins.However, the -helix can also be important in thestructure globular proteins, although those chains are

much shorter than the chains in fibrous proteins


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-Helix -Sheet


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Tertiary structurerefers to the spatialrelationships of more distant residues

1. Folding.The secondary ordered polypeptidechains of soluble proteins tend to fold into globularstructure with the hydrophobic side chain in theinterior of the structure away from the water andthe hydrophilic side chains on the outside in contactwith water. This folding is due to associationsbetween segments -helix, extended -chains, or

other secondary structures and represent a state oflowest energy (greatest stability)


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2. The conformation result from:

a. Hydrogen bonding within a chain or betweenchains

b. The flexibility of the chain at points ofinstability, allowing water to obtain maximum

entropy and thus govern the structure tosome extent

c. The formation of other non covalent bondsbetween side chain groups, such as salt

linkages, or -electron interaction of aromaticrings

d. The sites and numbers of disulfide bridgesbetween Cys residues within the chain


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Quartenary structure refers to the spatialrelationships between individual polypeptidechains in a multi chain protein; that is, thecharacteristic noncovalent interaction betweenthe chains that form the native conformation of

the protein as well as occasional disulfide bondsbetween the chains

1. Many proteins larger than 50 kdal have more thanone chain and are said to contain multiple subunits,

with individual chains known as protomers.2. Many multisubunit proteins are composed of different

kinds of functional subunits.


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Denaturation

Denaturation is the organization of theoverall molecular shape of a protein. Itcan occur as an unfolding of uncoilingof helices, or as separation of subunits.

Denaturation is usually is accompaniedby a major loss in solubility.

Several reagents or physical force like

heat, UV radiation, shaking, ethanol,heavy metals, and strong acids andbases that cause denaturation.


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denaturation

renaturation

Th d d i t t f


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The gene-encoded primary structure ofpolypeptide is the sequence of its aminoacids. Primary structure are stabilizedby covalent peptide bonds.

Its secondary structure results fromfolding of polypeptide into hydrogen-bonded motifs can form supersecondarymotifs. Secondary structure (higherorders) are stabilized by weak force-

multiple hydrogen bond, electrostaticbond (salt bond), and association ofhydrophobic R groups.

Tertiary structure concern therelationships between secondary

structure domains. Quartenary structure of proteins with

two or more polypeptides (oligometricproteins) is a feature based on thespatial relationships between various

types of polypeptide


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Protein can be classified according to solubility,shape or the presence of nonprotein groups, etc.

For example:1. Solubility, two major families are the globular andfibrous protein. The globular proteins are compact, areroughly spherical or ovoid in shape, and have axialratios of not over 3 (the ratio of their shortes to

longest dimention).2. Composition. For example: glycoproteins, lipoproteins,

metaloproteins (that incorporate a metal ion such asmany enzyme do) etc.

3.

Biologycal functions: enzymes, hormones,neurotransmitters, toxin, contractile muscle (myosinand actin), storage protein (casein, ovalbumin andferritin), transfort protein (hemoglobin), structuralproteins (collagen, elastine, and protein cell

membranes) and protective proteins.


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Globular Proteins

Myoglobin, a monomeric protein of redmuscle, stores oxygen.

Hemoglobin, a tetramic (22) protein oferitrocytes, transport O2 to the tissue and

return CO2 and rptons to the lung. Despitedifferent primary structures, the secondary-tertiary structure of subunits of hemoglobin(Hb S), Val replaces the 6 Glu of Hb A. The

genetic defect has known as thalassemiaresult from theh partial or total absence ofone or more or chains of hemoglobin.

MYOGLOBIN STRUCTURE


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MYOGLOBIN STRUCTURE


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Fibrous Proteins

Collagen is the most abundant of the fibrousproteins that constitute more than 25% of theprotein mass in the human body. Theseproteins in bone, teeth, tendons, skin, and softconnective tissue. Collagen forms a uniquetriple helix. Every third amino acid residue incollagen is a glycine residue. Collagen is alsorich in proline and hydroxyproline, yielding arepetitive Gly-X-Y pattern in which Y generally

is proline or hydroxyproline (Gly-X-Y-Gly-X-Y-Gly-X-Y-). Disease of collagen maturationinclude the vitamin C deficiency disease scurvyand Ehlers-Danlos syndrome.


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Prions-Protein

Human prionrelated protein, PrP, a glycoproteinencoded on the short arm of chromosome 20,normally is monomeric and rich helix.Pathologic prion proteins, known as PrPc, is richin sheet with many hydrophobic aminoacylside chains. Prion disease are proteinconformation diseases transmitted by alteringthe conformation, fatal neurogenerativediseases characterized by spongiform changes.

For example: Creutzfeld-Jacob disease inhumans, scrapie in sheep, and bovinespongiform encephalopathy (mad cow disease)in cattle.


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References:

Mathews, C.K., etc. 2000,Biochemistry, 3rd Edition, AddisonWesley Longman, Inc., California.

Murray, R.K., etc., 2003, HarpersIllustrated Biochemistry, 26th Ed.,McGraw-Hill, California.

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2006-Protein Structure and Function

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