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Thus, for example, the trypsinlike serine protease domain is linked to atleast 18 other types of protein domains in human proteins, whereas it is foundcovalently joined to only 5 different domains in the worm. This extra variety inour proteins greatly increasesthe range of protein-protein interactions possible(seeFigure 3-82), but how it contributes to making us human is not known.The complexity of living organisms is staggering,and it is quite sobering tonote that we currently lack even the tiniest hint of what the function might be formore than 10,000of the proteins that have thus far been identified in the humangenome.
There are certainly enormous challengesahead for the next generationof cell biologists, with no shortage of fascinating mysteries to solve.yeastZntEp1 PHD PHD Ep2BrEp1 PHD PHD Ep2BrBMBFigure3-19 Domainstructureof agroup of evolutionarilyrelated proteinsthat are thought to havea similarfunction.In general,thereis a tendencyfor the proteinsin morecomplexorganisms,suchas humans,to containadditionaldomains-as isthecasefor the DNA-bindingproteincomparedhere.LargerProteinMoleculesOftenContainMoreThanOnePolypeptideChain<cccr>The same weak noncovalent bonds that enable a protein chain to fold into a specific conformation also allow proteins to bind to each other to produce largerstructures in the cell. Any region of a protein's surface that can interact withanother molecule through sets of noncovalent bonds is called a binding site.
Aprotein can contain binding sites for various large and small molecules. If abinding site recognizesthe surface of a second protein, the tight binding of twofolded polypeptide chains at this site creates a larger protein molecule with aprecisely defined geometry. Each pollpeptide chain in such a protein is called aprotein subunit.In the simplest case, two identical folded polypeptide chains bind to eachother in a "head-to-head" arrangement, forming a symmetric complex of twoprotein subunits (a dimer) held together by interactions between two identicalbinding sites.
The cro repressor protein-a viral gene regulatory protein thatbinds to DNA to turn viral genes off in an infected bacteiial cell-provides anexample (Figure 3-20). cells contain many other types of s).rynmeiricproteincomplexes, formed from multiple copies of a single pollpeptide chain. Theenzyme neuraminidase, for example, consists of four identical protein subunits,each bound to the next in a "head-to-tail" arrangement that foims a closed ring(Figure 3-21).Many of the proteins in cells contain two or more tlpes of polypeptidechains. Hemoglobin, the protein that carries oxygen in red Llood ceils, cbntainsFigure3-20 Two identical proteinsubunitsbindingtogetherto form asymmetric protein dimer.The Crorepressorproteinfrom bacteriophagelambdabindsto DNAto turn off viralgenes.lts two identicalsubunitsbindhead-to-head,heldtogetherby acombinationof hydrophobicforces(blue)and a set of hydrogenbonds (yellowregion).(Adaptedfrom D.H.OhlendorlD.E.Tronrudand B.W.Matthews,J.
Mol.Biol.280:129-136,1998.Wirh permissionfrom AcademicPress.)THESHAPEAND STRUCTUREOF PROTEINSrl:.. :r.143Figure3-21 A protein moleculecontainingmultiplecopiesof a singleproteinsubunit.Theenzymeexistsas a ring of fourneuraminidaseidenticalpolypeptidechains.Eachofthesechainsis formed from six repeatsofp sheet,as indicatedbya four-strandedThe smalldiagramthe coloredarrows.showshow the repeateduseof the samebindinginteractionformsthe structure.t e t r a m e ro f n e u r a m i n i d a sper o t e i ntwo identical a-globin subunits and two identical B-globin subunits, symmetrically arranged (Figure 3-22). Such multisubunit proteins are very common incells, and they can be very large.
Figure 3-23 shows a sample of proteins whoseexact structures are knolnn, and it compares the sizesand shapesof a few largerproteins with some of the relatively small proteins that we have thus far presented as models.SomeProteinsFormLongHelicalFilamentsSome protein molecules can assemble to form filaments that may span theentire length of a cell. Most simply, a long chain of identical protein moleculescan be constructed if each molecule has a binding site complementary toanother region of the surface of the same molecule (Figure 3-24).
An actin filament, for example, is a long helical structure produced from many molecules ofthe protein actin (Figure3-2$). Actin is very abundant in eucaryotic cells,whereit constitutes one of the major filament systems of the cltoskeleton (discussedin Chapter 16).'vVhyis a helix such a common structure in biology? As we have seen, bioIogical structures are often formed by linking similar subunits-such as aminoacids or protein molecules-into long, repetitive chains. If all the subunits areidentical, the neighboring subunits in the chain can often fit together in onlyone way, adjusting their relative positions to minimize the free energy of thecontact between them.
As a result, each subunit is positioned in exactly thesame way in relation to the next, so that subunit 3 fits onto subunit 2 in the sameway that subunit 2 fits onto subunit 1, and so on. Becauseit is very rare for subunits to join up in a straight line, this arrangement generally results in a helixa regular structure that resemblesa spiral staircase,as illustrated in Figure 3-26'Depending on the twist of the staircase,a helix is said to be either right-handedor left-handed (see Figure 3-26E).
Handedness is not affected by turning thehelix upside dourn, but it is reversed if the helix is reflected in the mirror.Figure 3-22 A protein formed as asymmetricassemblyof two differentsubunits.Hemoglobinis an abundantoroteinin red bloodcellsthat containstwocopiesof o-globinand two copiesofB-globin.Eachof thesefour polypeptidechainscontainsa hememolecule(red)which is the sitethat bindsoxygen(Oz).Thus,eachmoleculeof hemoglobinin thebloodcarriesfour moleculesof oxygen."144Chapter3: Proteins5H2domainlysozymecatalasemyoglobindeoxyribonucleasecytochromecponnchymotrypsincalmodulininsulinFigure3-23 A collectionof protein molecules,shown at the same scale.Forcomparison,a DNA moleculebound to a protein is alsoillustrated.Thesespace-fillingmodelsrepresenta rangeof sizesand shapes.Hemoglobin,catalase,porin,alcoholdehyd'rogenase,andaspartatetranscarbamoylaseareformed from multiple copiesof subunits.The SH2domain (topteft)is presentedin detail in panel3-2(pp.132-133).(Adaptedfrom David5.
Goodsell,Our MolecularNature.NewYork:Springer-Veriag,t SSO.Witn permissionfrom SpringerScienceand BusinessMedia.)THESHAPEAND STRUCTUREOF PROTEINS(A)a s s e m b l e sdt r u c t u r e sfree..s uD Un r t s(B), .i, . . , , , , . . : i ,il :i ,1.4' ,5,Figure3-24 Proteinassemblies.(A)A proteinwith just one bindingsitecanform a dimerwith anotheridenticalprotein.(B)ldenticalproteinswith twodifferentbinding sitesoften form a longhelicalfilament.(C)lf the two bindinginsitesaredisposedappropriatelyrelationto eachother,the proteinsubunitsmayform a closedring insteadof a helix.(Foran exampleof A, seeFigure3-20;for an exampleof C,seeF i g u r e3 - 2 1 .
)-Helices occur commonly in biological structures, whether the subunits aresmall molecules linked together by covalent bonds (for example, the aminoacids in an u helix) or large protein molecules that are linked by noncovalentforces (for example, the actin molecules in actin filaments). This is not surprising. A helix is an unexceptional structure, and it is generated simply by placingmany similar subunits next to each other, each in the same strictly repeated relationship to the one before-that is, with a fixed rotation followed by a fixedtranslation along the helix axis, as in a spiral staircase.a c t i nm o l e c u l em i n u se n dFibrousShapesHaveElongated,ManyProteinMoleculesMost of the proteins that we have discussedso far areglobular proteins,in whichthe pollpeptide chain folds up into a compact shape like a ball with an irregularsurface.
Enzymes tend to be globular proteins: even though many are large andcomplicated, with multiple subunits, most have an overall rounded shape (seeFigure 3-23). In contrast, other proteins have roles in the cell that require eachindividual protein molecule to span a large distance. These proteins generallyhave a relatively simple, elongated three-dimensional structure and are commonly referred to as fibrous proteins.One large family of intracellular fibrous proteins consists of cr-keratin,introduced when we presented the cxhelix, and its relatives. Keratin filaments areextremely stable and are the main component in long-lived structures such ashair.
horn, and nails. An cx-keratinmolecule is a dimer of two identical subunits,with the long c helices of each subunit forming a coiled-coil (see Figure 3-9).The coiled-coil regions are capped at each end by globular domains containingbinding sites.This enables this class of protein to assemble into ropelike intermediate filaments-an important component of the cltoskeleton that createsthe cell's internal structural framework (seeFigure 16-19).Fibrous proteins are especially abundant outside the cell, where they are amain component of the gel-like extracellular matrix that helps to bind collections of cells together to form tissues.Cells secreteextracellular matrix proteinsinto their surroundings, where they often assemble into sheets or long fibrils.)l)1:znmllip l u se n d(A)50"m(B)Figure3-25 Actin filaments'(A)Transmissionelectronmicrographsof negativelystainedactin filaments.(B)The helicalarrangementof actinmoleculesin an actinfilament.(A,courtesyof RogerCraig.,146Chapter3: Proteinslefthanded(E)(A)(B)(c)Figure3-26 Somepropertiesof a helix.(A-D) A helixformswhen a seriesofsubunitsbind to eachother in a regularway.At the bottom,the interactionbetweentwo subunitsis shown;behindthem arethe helicesthat result.Theseheliceshavetwo (A),three(B),and six(Cand D) subunitsper helicalturn.Thephotographsat the top showthearrangementof subunitsviewedfromdirectlyabovethe helix.Notethat thehelixin (D)hasa wider path than that in(C),but the samenumberof subunitsperturn.(E)A helixcan be eitherrighthandedor left-handed.As a reference,itis usefulto rememberthat standardmetalscrews,which insertwhen turnedclockwise,areright-handed.Notethat arighthelixretainsthe samehandednesswhenhandedit isturnedupsidedown.(D)collagen is the most abundant of these proteins in animal tissues.A collagenmolecule consists of three long pollpeptide chains, each containing the nonpolar amino acid glycine at every third position.
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