Chapter3 Structure and function relationships of proteins.ppt

Chapter3StructureandFunctionRelationshipsofProteins,Outline,FunctionsofproteinsStructureandfunctionrelationshipsofproteinsGeneralprinciplesofstructure-functionrelationshipsofproteinsSeveralimportantproteins:structure-functionrelationshipsProteinfunctionprediction,ProteinsaretheagentsofbiologicalfunctionEnzymes-RibonucleaseSignaltransductionInsulinanditsreceptorControlofGeneexpression-TranscriptionfactorsImmunity-AntibodyTransportandStorage-HemoglobinStructuralproteinsHair,CollagenContractileproteins-Actin,MyosinExoticproteins-AntifreezeproteinsinfishMoonlightingproteins,BiologicalFunctionsofProteins,Moonlightingproteinsareproteinsthathavesecondary("hidden")functionsinadditiontotheirprimaryfunctions.Manyglycolyticproteinshavemoonlightingactivities.Aspecialclassofmoonlightingproteinsaretriggerenzymesthatcontrolgeneexpressioninadditiontotheirenzymaticfunction.Anexample:Glyceraldehyde-3-phosphatedehydrogenasecandoubleasuracilDNAglycosylase.,Moonlightingproteins,FunctionisderivedfromstructureStructureisderivedfromsequenceSimilarsequenceshavesimilarfunctionsSimilarfunctionoftenimpliesevolutionaryrelatednessSequencesimilaritysuggestscommonevolutionaryoriginManydiseasesarerelatedtoanomalyofsomeproteins-Cysticfibrosis,sicklecellanemiaandmadcowdisease,Structure-functionrelationship,human,yeast,mouse,plant,Andmanyotherdifferentorganisms,Onceuponatime,therewerescientiststhatstudied,EvolutionandProteinSequenceHomology,Theybelievedthatdifferentorganismscarriedoutverydifferentbiochemicalreactions,hmmseemslikedifferentorganismssharesimilarbiochemicalprocesseswell,seemslikeproteinsinchargeofthesimilarbiochemicalprocessesindifferentorganismsaresimilarinmanywayse.g.size,pIetce.g.cytochromecinrespirationpeoplewereshockedwhentheysawthesequencesofcytochromecfromdifferentorganisms,Butslowlyandslowlytheyrealized,Comparisonofcytochromecsequences,50aminoaciddifferenceSequenceisknowninover80species,bacteria,bacteria,fish,similarsequences-similarstructures-samefunction,Cytochromec,Foundinallspeciesthatuseoxygen:bacteria-humansMosthave104aminoacids,26/104invariantEvolved>1.5billionyearsago,beforedivergenceofplantsandanimals#aminoacidsdifferencesbetween2speciesproportionaltotimeofevolutionarydivergenceAminoaciddifferencesarenotrandomAminoaciddifferencessurvivednaturalselection,Whatcanbelearnedfromaminoacidsequenceofcytochromec?,ThenumberofaminoaciddifferencesbetweentwocytochromecsequencesisproportionaltothephylogeneticdifferencebetweenthespeciesfromwhichtheyarederivedThisobservationcanbeusedtobuildphylogenetictreesofproteinsThisisthebasisforstudiesofmolecularevolution,PhylogenyofCytochromec,Phylogenetictreesofcytochromec,AnalogousproteinsandHomologousproteins,Analogousproteins:similarorsamefunctionwithdifferentsequence,evolvedfromdifferentancestorHomologousproteinsSimilarsequence,Similarstructure,Similarfunction,EvolvedfromcommonancestorHomolog:orthologandparalog,Homolog:orthologandparalog,MuchormostofthepolypeptidechainisorganizedapproximatelyparalleltoasingleaxisFibrousproteinsareoftenmechanicallystrongFibrousproteinsareusuallyinsolubleUsuallyplayastructuralroleinnature,FibrousProteins,ProteinsthatformextensiveAlphahelicesFoundinhair,fingernails,claws,hornsandbeaksSequenceconsistsof311-314residuealphahelicalrodsegmentscappedwithnon-helicalN-andC-terminiPrimarystructureofhelicalrodsconsistsof7-residuerepeats:(a-b-c-d-e-f-g)n,whereaanddarenonpolar.Promotesassociationofhelices!,AlphaKeratin,Hierarchyofalpha-keratinstructure,Biochemicalprinciplesofhairperming/straightening,ProteinsthatformextensivebetasheetsFoundinsilkfibersAlternatingsequence:Gly-Ala/Ser-Gly-Ala/Ser.Sinceresiduesofabetasheetextendalternatelyaboveandbelowtheplaneofthesheet,thisplacesallglycinesononesideandallalaninesandserinesonotherside!ThisallowsGlysononesheettomeshwithGlysonanadjacentsheet(sameforAla/Sers),BetaKeratin,Hierarchyofbeta-keratinstructure,Beta-sheetsfoundinbeta-keratin,Principalcomponentofconnectivetissue(tendons,cartilage,bones,teeth)basicunitistropocollagen:threeintertwinedpolypeptidechains(1000residueseachMW=285000300nmlong,1.4nmdiameteruniqueaminoacidcomposition,Collagen-ATripleHelix,ThesecretsofitsAAcomposition.NearlyoneresidueoutofthreeisGlyProlinecontentisunusuallyhighUnusualaminoacidsfound:4-hydroxyproline3-hydroxyproline5-hydroxylysineProandHyProtogethermake30%ofrest.,Collagen,Theanswer:Introduceextrahydrogenbonddonors(-OH)tostabilizethetriplehelix,Themodificationsarecatalyzedbyhydroxylase.ThehydroylationrequiresO2,-ketoglutarate,andascorbicacid(vitaminC).andisactivatedbyFe2+.VitaminChelpstokeepironintheferrousstate,soitsdeficiencycancauseScurvy.,WhyhastohydroxylateProorLys?,AcaseofstructurefollowingcompositionTheunusualaminoacidcompositionofcollagenisunsuitedforalphahelicesORbetasheetsButitisideallysuitedforthecollagentriplehelix:threeintertwinedhelicalstrandsMuchmoreextendedthanalphahelix,withariseperresidueof0.29nm3.3residuesper,TheCollagenTripleHelix,Triple-helixconformationGlymustoccupyeverythirdresidueNosidechainsSmallenoughtofitinsidethehelixGlyalignedwithXresidueofonechainandYresidueofthirdchainStaggeredarrangementinhelixbyoneresidueMutationthatcausesreplacementofGlyleadstodefectivemoleculesanddiseaseOsteogenesisImperfecta,PolypeptideChains,Everythirdresiduefacesthecrowdedcenterofthehelix-onlyGlyfitshereProandHyPsuittheconstraintsofphiandpsiInterchainH-bondsinvolvingHyPstabilizehelixFibrilsarefurtherstrengthenedbyintrachainlysine-lysineandinterchainhydroxypyridiniumcrosslinks,Structuralbasisofthecollagentriplehelix,CollagenfibersarestabilizedandstrengthenedbyLys-lyscross-linksorMet-Hyl-sulfiliminelinks.,TripleHelix,CollagenStructures,BromineIsanEssentialTraceElementforAssemblyofCollagenIVScaffoldsinTissueDevelopmentandArchitecture(Cell157,13801392,June5,2014),Myoglobinandhemoglobinaretwoofthemost-studiedandbest-understoodproteinsinallofbiochemistry.Thesearethefirsttwoproteinstohavetheir3DstructuressolvedbyX-raydiffractionmethods,whichrepresentedamilestoneinbiochemistry.Theseproteinswerecrucialintheconversionofanaerobiclifetoaerobiclife.Aerobicmetabolismyieldsmuchmoreenergythananaerobicmetabolism.Allowedformorecomplexlifeformstoevolve.Problem:Oxygenhaslimitedsolubilityinwater.Itisinfactahydrophobicmolecule.Needawaytobindoxygeneffectively,inordertodeliverittotissuesinsufficientquantities.Proteinslikemyoglobinandhemoglobinevolvedtofulfillthatpurpose.,MyoglobinLowlevelofdisorderedproteininMitochondriaCanpredictwhetherornotaproteinwillfoldusingthiswebsite:FoldIndex,CharacteristicsofUCPs,AdvantagesofUCPs,MoremalleablewithrespecttoregulationandbindingofligandsAbletobindseveraldifferentligandsHavelargeintermolecularinterfacesOverallsmallerproteingenomeandcellsizesSomenativelyunfoldedproteinswraparoundtheirpartneruponbindingandgainastructuredformation,FunctionofUCPsinthecell,Primarilyassociatedwithsignaltransduction,cell-cycleregulation,andgeneexpressionBindingofDNAtofacilitatetranscription,transposition,packaging,repair,andreplicationAssociatedwithsitesofpost-translationalmodificationFrequentinRNAandproteinchaperones,FunctionsofsomeNUPs,Sequence-basedApproachesStructure-basedApproachesAlignmentOfStructureandSequenceMotif-basedApproachesGuilt-by-association,ProteinFunctionPrediction,