Chapter3 Structure and function relationships of proteins.ppt

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1、Chapter3StructureandFunctionRelationshipsofProteins,Outline,FunctionsofproteinsStructureandfunctionrelationshipsofproteinsGeneralprinciplesofstructure-functionrelationshipsofproteinsSeveralimportantproteins:structure-functionrelationshipsProteinfunctionprediction,Proteinsaretheagentsofbiologicalfunc

2、tionEnzymes-RibonucleaseSignaltransductionInsulinanditsreceptorControlofGeneexpression-TranscriptionfactorsImmunity-AntibodyTransportandStorage-HemoglobinStructuralproteinsHair,CollagenContractileproteins-Actin,MyosinExoticproteins-AntifreezeproteinsinfishMoonlightingproteins,BiologicalFunctionsofPr

3、oteins,Moonlightingproteinsareproteinsthathavesecondary(hidden)functionsinadditiontotheirprimaryfunctions.Manyglycolyticproteinshavemoonlightingactivities.Aspecialclassofmoonlightingproteinsaretriggerenzymesthatcontrolgeneexpressioninadditiontotheirenzymaticfunction.Anexample:Glyceraldehyde-3-phosph

4、atedehydrogenasecandoubleasuracilDNAglycosylase.,Moonlightingproteins,FunctionisderivedfromstructureStructureisderivedfromsequenceSimilarsequenceshavesimilarfunctionsSimilarfunctionoftenimpliesevolutionaryrelatednessSequencesimilaritysuggestscommonevolutionaryoriginManydiseasesarerelatedtoanomalyofs

5、omeproteins-Cysticfibrosis,sicklecellanemiaandmadcowdisease,Structure-functionrelationship,human,yeast,mouse,plant,Andmanyotherdifferentorganisms,Onceuponatime,therewerescientiststhatstudied,EvolutionandProteinSequenceHomology,Theybelievedthatdifferentorganismscarriedoutverydifferentbiochemicalreact

6、ions,hmmseemslikedifferentorganismssharesimilarbiochemicalprocesseswell,seemslikeproteinsinchargeofthesimilarbiochemicalprocessesindifferentorganismsaresimilarinmanywayse.g.size,pIetce.g.cytochromecinrespirationpeoplewereshockedwhentheysawthesequencesofcytochromecfromdifferentorganisms,Butslowlyands

7、lowlytheyrealized,Comparisonofcytochromecsequences,50aminoaciddifferenceSequenceisknowninover80species,bacteria,bacteria,fish,similarsequences-similarstructures-samefunction,Cytochromec,Foundinallspeciesthatuseoxygen:bacteria-humansMosthave104aminoacids,26/104invariantEvolved1.5billionyearsago,befor

8、edivergenceofplantsandanimals#aminoacidsdifferencesbetween2speciesproportionaltotimeofevolutionarydivergenceAminoaciddifferencesarenotrandomAminoaciddifferencessurvivednaturalselection,Whatcanbelearnedfromaminoacidsequenceofcytochromec?,Thenumberofaminoaciddifferencesbetweentwocytochromecsequencesis

9、proportionaltothephylogeneticdifferencebetweenthespeciesfromwhichtheyarederivedThisobservationcanbeusedtobuildphylogenetictreesofproteinsThisisthebasisforstudiesofmolecularevolution,PhylogenyofCytochromec,Phylogenetictreesofcytochromec,AnalogousproteinsandHomologousproteins,Analogousproteins:similar

10、orsamefunctionwithdifferentsequence,evolvedfromdifferentancestorHomologousproteinsSimilarsequence,Similarstructure,Similarfunction,EvolvedfromcommonancestorHomolog:orthologandparalog,Homolog:orthologandparalog,MuchormostofthepolypeptidechainisorganizedapproximatelyparalleltoasingleaxisFibrousprotein

11、sareoftenmechanicallystrongFibrousproteinsareusuallyinsolubleUsuallyplayastructuralroleinnature,FibrousProteins,ProteinsthatformextensiveAlphahelicesFoundinhair,fingernails,claws,hornsandbeaksSequenceconsistsof311-314residuealphahelicalrodsegmentscappedwithnon-helicalN-andC-terminiPrimarystructureof

12、helicalrodsconsistsof7-residuerepeats:(a-b-c-d-e-f-g)n,whereaanddarenonpolar.Promotesassociationofhelices!,AlphaKeratin,Hierarchyofalpha-keratinstructure,Biochemicalprinciplesofhairperming/straightening,ProteinsthatformextensivebetasheetsFoundinsilkfibersAlternatingsequence:Gly-Ala/Ser-Gly-Ala/Ser.S

13、inceresiduesofabetasheetextendalternatelyaboveandbelowtheplaneofthesheet,thisplacesallglycinesononesideandallalaninesandserinesonotherside!ThisallowsGlysononesheettomeshwithGlysonanadjacentsheet(sameforAla/Sers),BetaKeratin,Hierarchyofbeta-keratinstructure,Beta-sheetsfoundinbeta-keratin,Principalcom

14、ponentofconnectivetissue(tendons,cartilage,bones,teeth)basicunitistropocollagen:threeintertwinedpolypeptidechains(1000residueseachMW=285000300nmlong,1.4nmdiameteruniqueaminoacidcomposition,Collagen-ATripleHelix,ThesecretsofitsAAcomposition.NearlyoneresidueoutofthreeisGlyProlinecontentisunusuallyhigh

15、Unusualaminoacidsfound:4-hydroxyproline3-hydroxyproline5-hydroxylysineProandHyProtogethermake30%ofrest.,Collagen,Theanswer:Introduceextrahydrogenbonddonors(-OH)tostabilizethetriplehelix,Themodificationsarecatalyzedbyhydroxylase.ThehydroylationrequiresO2,-ketoglutarate,andascorbicacid(vitaminC).andis

16、activatedbyFe2+.VitaminChelpstokeepironintheferrousstate,soitsdeficiencycancauseScurvy.,WhyhastohydroxylateProorLys?,AcaseofstructurefollowingcompositionTheunusualaminoacidcompositionofcollagenisunsuitedforalphahelicesORbetasheetsButitisideallysuitedforthecollagentriplehelix:threeintertwinedhelicals

17、trandsMuchmoreextendedthanalphahelix,withariseperresidueof0.29nm3.3residuesper,TheCollagenTripleHelix,Triple-helixconformationGlymustoccupyeverythirdresidueNosidechainsSmallenoughtofitinsidethehelixGlyalignedwithXresidueofonechainandYresidueofthirdchainStaggeredarrangementinhelixbyoneresidueMutation

18、thatcausesreplacementofGlyleadstodefectivemoleculesanddiseaseOsteogenesisImperfecta,PolypeptideChains,Everythirdresiduefacesthecrowdedcenterofthehelix-onlyGlyfitshereProandHyPsuittheconstraintsofphiandpsiInterchainH-bondsinvolvingHyPstabilizehelixFibrilsarefurtherstrengthenedbyintrachainlysine-lysin

19、eandinterchainhydroxypyridiniumcrosslinks,Structuralbasisofthecollagentriplehelix,CollagenfibersarestabilizedandstrengthenedbyLys-lyscross-linksorMet-Hyl-sulfiliminelinks.,TripleHelix,CollagenStructures,BromineIsanEssentialTraceElementforAssemblyofCollagenIVScaffoldsinTissueDevelopmentandArchitectur

20、e(Cell157,13801392,June5,2014),Myoglobinandhemoglobinaretwoofthemost-studiedandbest-understoodproteinsinallofbiochemistry.Thesearethefirsttwoproteinstohavetheir3DstructuressolvedbyX-raydiffractionmethods,whichrepresentedamilestoneinbiochemistry.Theseproteinswerecrucialintheconversionofanaerobiclifet

21、oaerobiclife.Aerobicmetabolismyieldsmuchmoreenergythananaerobicmetabolism.Allowedformorecomplexlifeformstoevolve.Problem:Oxygenhaslimitedsolubilityinwater.Itisinfactahydrophobicmolecule.Needawaytobindoxygeneffectively,inordertodeliverittotissuesinsufficientquantities.Proteinslikemyoglobinandhemoglob

22、inevolvedtofulfillthatpurpose.,MyoglobinLowlevelofdisorderedproteininMitochondriaCanpredictwhetherornotaproteinwillfoldusingthiswebsite:FoldIndex,CharacteristicsofUCPs,AdvantagesofUCPs,MoremalleablewithrespecttoregulationandbindingofligandsAbletobindseveraldifferentligandsHavelargeintermolecularinte

23、rfacesOverallsmallerproteingenomeandcellsizesSomenativelyunfoldedproteinswraparoundtheirpartneruponbindingandgainastructuredformation,FunctionofUCPsinthecell,Primarilyassociatedwithsignaltransduction,cell-cycleregulation,andgeneexpressionBindingofDNAtofacilitatetranscription,transposition,packaging,repair,andreplicationAssociatedwithsitesofpost-translationalmodificationFrequentinRNAandproteinchaperones,FunctionsofsomeNUPs,Sequence-basedApproachesStructure-basedApproachesAlignmentOfStructureandSequenceMotif-basedApproachesGuilt-by-association,ProteinFunctionPrediction,