Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24 英文参考文献.docVIP

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Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24 英文参考文献.doc

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Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24 英文参考文献

RequirementsforEfficientProteolyticCleavageof PrelaminAbyZMPSTE24 JemimaBarrowman,CorinneHamblet,MeganS.Kane,SusanMichaelis* DepartmentofCellBiology,TheJohnsHopkinsSchoolofMedicine,Baltimore,Maryland,UnitedStatesofAmerica Abstract Background:TheproteolyticmaturationofthenuclearproteinlaminAbythezincmetalloproteaseZMPSTE24iscriticalfor human health. The lamin A precursor, prelamin A, undergoes a multi-step maturation process that includes CAAX processing (farnesylation, proteolysis and carboxylmethylation of the C-terminal CAAX motif), followed by ZMPSTE24- mediatedcleavageofthelast15aminoacids,includingthemodifiedC-terminus.FailuretocleavetheprelaminA‘‘tail’’,due tomutationsineitherprelaminAorZMPSTE24,resultsinapermanentlyprenylatedformofprelaminAthatunderliesthe prematureagingdiseaseHutchinson-GilfordProgeriaSyndrome(HGPS)andrelatedprogeroiddisorders. Methodology/PrincipalFindings:HerewehaveinvestigatedthefeaturesoftheprelaminAsubstratethatarerequiredfor efficientcleavagebyZMPSTE24.WefindthattheC-terminal41aminoacidsofprelaminAcontainsufficientcontexttoallow cleavage of the tail by ZMPSTE24. We have identified several mutations in amino acids immediately surrounding the cleavagesite(betweenY646andL647)thatinterferewithefficientcleavageoftheprelaminAtail;thesemutationsinclude R644C,L648AandN650A,inadditiontothepreviouslyreportedL647R.Ourdatasuggeststhat9ofthe15residueswithin thecleavedtailthatlieimmediatelyupstreamoftheCAAXmotifarenotcriticalforZMPSTE24-mediatedcleavage,asthey canbereplacedbythe9aminoacidHAepitope.However,duplicationofthesame9aminoacids(toincreasethedistance betweentheprenylgroupandthecleavagesite)impairstheabilityofZMPSTE24tocleaveprelaminA. Conclusions/Significance:OurdatarevealsaminoacidpreferencesflankingtheZMPSTE24cleavagesiteofprelaminAand suggeststhatspacingfromthefarnesyl-cysteinetothecleavagesiteisimportantforoptimalZMPSTE24cleavage.These studiesbegintoelucidatethesubstraterequirementsofanenzymeactivitycriticaltohumanhealthandlongevity. C