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Note that the protein domain illustrated in Panel 3-2 contains two shelices,aswell asa three-strandedantiparallelB sheet.Regionsof a helix are especiallyabundantin proteinslocatedin cell membranes,such as transportproteinsand receptors.As we discussin Chapter10,thoseportions of a transmembraneprotein that crossthe lipid bilayer usuallycrossas an a helix composedlargelyof amino acidswith nonpolarsidechains.to itselfinThe pollpeptidebackbone,which is hydrophilic,is hydrogen-bondedthe crhelix and shieldedfrom the hydrophobiclipid environmentof the membraneby its protrudingnonpolarsidechains(seealsoFigure3-78).In other proteins,crheliceswrap around eachother to form a particularlystable structure,known as a coiled-coil.
This structure can form when the two(or in some casesthree) crheliceshave most of their nonpolar (hydrophobic)sidechainson one side,so that they can twist aroundeachotherwith thesesidechainsfacinginward (Figure3-9). Long rodlike coiled-coilsprovidethe structural framework for many elongatedproteins. Examplesare cr-keratin,whichforms the intracellular fibers that reinforce the outer layer of the skin and itsand the myosinmoleculesresponsiblefor musclecontraction.appendages,ProteinDomainsAreModularUnitsfrom whichLargerProteinsAre BuiltFigure3-8 Two tYPesof P sheetstructures.(A)An antiparallelB sheet(seeFigure3-7D).(B)A parallelB sheet.Both of these structuresare commonin oroteins.Even a small protein molecule is built from thousands of atoms linked together byprecisely oriented covalent and noncovalent bonds, and it is extremely difficult tovisualize such a complicated structure without a three-dimensional display.
ForNHzNHzs t r i p eo fhydrophobic, , a , 'a n d , , d , ,aminoacidsHOOC COOH(B)(c)Figure3-9 A coiled-coil.<CGGA>amino(A)A singleo helix,with successiveacidsidechainslabeledin a sevenfoldsequence,"abcdefg"(from bottom to top)'Aminoacids"a"and'd" in sucha sequencelie closetogetheron the cylindersurface,forming a "stripe"(red)that winds slowlythat formaroundthe o helix.Proteinstypicallyhavenonpolaraminocoiled-coilsacidsat positions"a"and "dl'Consequently,as shown in (B),the two cr helicescan wraparoundeachotherwith the nonpolarsidewith thechainsof one s helixinteractingnonpolarsidechainsof the other,whilethemore hydrophilicaminoacidsidechainsareleft exposedto the aqueousenvironment'(C)The atomic structureof a coiled-coilThedeterminedby x-raycrystallography.red sidechainsare nonPolar'136Chapter3: Proteinsthis reason,biologists use various graphic and computer-based aids.A DVD thataccompanies this book contains computer-generated images of selected proteins, displayed and rotated on the screen in a variety of formats.Biologists distinguish four levels of organization in the structure of a protein.The amino acid sequence is knor,t'n as the primary structure.
Stretches ofpolypeptide chain that form c helices and p sheets constitute the protein's secondary structure. The full three-dimensional organization of a polypeptidechain is sometimes referred to as the tertiary structure, and if a paiticuiaiprotein molecule is formed as a complex of more than one polypepiide chain, thecomplete structure is designated as the quaternary structure.Studies of the conformation, function, and evolution of proteins have alsorevealed the central importance of a unit of organization distinct from thesefour. This is the protein domain, a substructure produced by any part of apolypeptide chain that can fold independently into i compact, itable s1.uctu.e.A domain usually contains between 40 and 350 amino acids, and it is the modular unit from which many larger proteins are constructed.The different domains of a protein are often associatedwith different functions.
Figure 3-10 shows an example-the Srcprotein kinase,which functions insignaling pathways inside vertebrate cells (src is pronounced "sarc',).This protein is considered to have three domains: the sH2 and sH3 domains have regulatory roles, while the c-terminal domain is responsible for the kinase catalyticactivity. Later in the chapter, we shall return to this protein, in order to expiainhow proteins can form molecular switches that transmit information throughout cells.Figure 3-ll presents ribbon models of three differently organized protein_domains.
As these examples illustrate, the pollpeptide chain tends to cross theentire domain before making a sharp turn at the surface. The central core of adomain can be constructed from crhelices, from B sheets,or from various combinations of these two fundamental folding elements. <CAGT>The smallest protein molecules contain only a single domain, whereaslarger proteins can contain as many as several d,ozendomiins, often connectedto each other by short, relatively unstructured lengths of pollpeptide chain.Fewof the ManyPossiblepolypeptidechainswiil Be usefuttoCe l l sSince each of the 20 amino acids is chemically distinct and each can, in principle, occur at any position in a protein chain, there are 20 x 20 x 20 x 20 = 160,000different possible polypeptide chains four amino acids long, or 20n differentpossible polypeptide chains n amino acids long.
For a typical protein lengthofS H 3d o m a i nS H 2d o m a i nFigure3-10 A proteinformed frommultipledomains.In the Srcproteinshown,a C-terminaldomainwith twolobes(yel/owand orange)forms a proteinkinaseenzyme,whilethe SH2and SH3domainsperformregulatoryfunctions.(A)A ribbon model,with ATPsubstrateinred.(B)A spacing-fillingmodel,with ATpsubstratein red.Note that the site thatbindsATPis positionedat the interfaceofthe two lobesthat form the kinase.Thedetailedstructureof the SH2domainisillustratedin Panel3-2 (pp.132-133).:,.,,.,.r',,r,,.THESHAPEAND STRUCTUREOFPROTEINSu(c)about 300 amino acids, a cell could theoretically make more than 103e0(20soo,different pollpeptide chains. This is such an enormous number that to producejust one molecule of each kind would require many more atoms than exist in theuniverse.Only a very small fraction of this vast set of conceivable polypeptide chainswould adopt a single, stable three-dimensional conformation-by some estimates, less than one in a billion.
And yet the vast majority of proteins present incells adopt unique and stable conformations. How is this possible?The answerIies in natural selection. A protein with an unpredictably variable structure andbiochemical activity is unlikely to help the survival of a cell that contains it. Suchproteins would therefore have been eliminated by natural selection through theenormously long trial-and-error process that underlies biological evolution.Becauseevolution has selectedfor protein function in living organisms, theamino acid sequence of most present-day proteins is such that a single conformation is extremely stable.
In addition, this conformation has its chemical properties finely tuned to enable the protein to perform a particular catalltic orstructural function in the cell. Proteins are so precisely built that the change ofeven a few atoms in one amino acid can sometimes disrupt the structure of thewhole molecule so severelvthat all function is lost.into ManyFamiliesProteinsCanBeClassifiedteins can be grouped into protein families, each family member having anamino acid sequence and a three-dimensional conformation that resemblethose of the other family members.Consider, for example, Ihe serine proteases,alarge family of protein-cleavingin their polypeptide chains, which are severalhundred amino acids long, are virtually ideniiiai lfig,rre 3-12).The many different serine proteases nevertheless.,,,,,.. 137Figure3-11 Ribbonmodelsof threedifferent protein domains.(A)Cytochromea single-domainb562,proteininvolvedin electrontransportinThisproteinis composedmitochondria.(B)Thealmostentirelyof o helices.domainof the enzYmeNAD-bindingwhich is composedlacticdehydrogenase,of a mixtureof o helicesand parallelpsheets.(C)Thevariabledomainof animmunoglobulin(antibody)light chain,composedof a sandwichof twop sheets.In theseexamples,antiparallelthe crhelicesareshownin green,whilestrandsorganizedas P sheetsaredenoted by redanows.chainNote how the polYPePtidebackand forth acrossgenerallytraversesthe entiredomain,makingsharpturnslt is theonly at the proteinsurface.protrudingloop regions(yellow)thatoften form the binding sitesfor other(Adaptedfrom drawingsmolecules.courtesyof JaneRichardson.)138Chapter3: ProteinsFigure3-12 A comparisonof theconformationsof two serineproteases.The backboneconformationsof elastaseand chymotrypsin.Althoughonlythoseaminoacidsin the polypeptidechainshadedin greenarc the samein the twoproteins,the two conformationsareverysimilarnearlyeverywhere.The activesiteof eachenzymeis circledin red;this iswherethe peptidebondsof the proteinsthat serveassubstratesare boundandcleavedby hydrolysis.The serineproteasesderivetheir namefrom theaminoacidserine,whosesidechainispart of the activesite of eachenzymeand directlyparticipatesin thecleavaqereaction.have distinct enzyrnatic activities, each cleaving different proteins or the peptide bonds between different types of amino acids.
Each therefore performs adistinct function in an organism.The story we have told for the serine proteases could be repeated for hundreds of other protein families. In general, the structure of the different members of a protein family has been more highly conserved than has the amino aciddom process, there must also have been many deleterious changes that alteredthe three-dimensional structure of these proteins sufficiently io harm them.(A)bL{h e l i x2(c)yeastGHRFTKENVRIRTAFSSEOLARDrosophilaLESWFAKNIENPYLDTKGLENLMKNTSL5LKREFNEN.--R\TTERRRQQLSSELGLNFigure3-13 A comparisonof a classofDNA-bindingdomains,calledhomeodomains,in a pair of proteinsfrom two organismsseparatedby morethan a billion yearsof evolution.(A)A ribbon model of the structurecommon to both proteins.(B)A traceofthe o-carbonpositions.Thethreedimensionalstructuresshownweredeterminedby x-raycrystallographyforthe yeastDrosophila engrailed protein (red).(C)A comparisonof aminoacidsequencesfor the regionof the proteinsshown in (A)and (B).Blackdotsmark siteswith identicalaminoacids.Orangedotsindicatethe positionof a threeaminoacidinsertin the cr2protein.(Adaptedfrom C.Wolbergeret al.,-528, 1991.With permissionCell67:5'17from Elsevier.)139ANDSTRUCTURT H ES H A P EOEF P R O T E I N SSuch faulty proteins would have been lost whenever the individual organismsmaking them were at enough of a disadvantage to be eliminated by naturalselection.Protein families are readily recognizedwhen the genome of any organism issequenced; for example, the determination of the DNA sequence for the entirehuman genome has revealedthat we contain about 24,000protein-coding genes.Through sequencecomparisons,we can assignthe products of about 40 percentof these genesto known protein structures,belonging to more than 500 differentprotein families.
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