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1、INSIGHTelifesciences.orgRECEPTORSIGNALINGClosinginonamechanismforactivationWheninsulin-likegrowthfactor-1(IGF1)bindstoitsreceptor,aphysicalconstraintisreleasedthatallowsthetwotransmembranehelicestocometogethertofacilitateactivationofthereceptor.STEVANRHUBBARDANDWTODDMILLERactivates
2、theintracellularkinasedomainhasbeenthesubjectofovertwodecadesofresearch(LemmonandSchlessinger,2010).RelatedresearcharticleKavranJM,Formostproteins(orligands)thatarerecog-McCabeJM,ByrnePO,ConnacherMK,nizedbyreceptortyrosinekinases,ligandbindingWangZ,RamekA,SarabipourS,ShanY,totherec
3、eptorbringstogethertworeceptorpro-ShawDE,HristovaK,ColePA,LeahyDJ.teinstoworkasa‘dimer’tosendasignalintothecell.However,theinsulinreceptorandIGF12014.HowIGF-1activatesitsreceptor.eLifereceptor(togetherwithareceptorknownas‘insu-3:e03772.doi:10.7554/eLife.03772linreceptor-relatedrece
4、ptor’)areuniqueamongImageMechanismofreceptorreleasereceptortyrosinekinasesinthattheyarepre-uponligand(insulinorIGF1)bindingformedintochemically(disulfide)-linkeddimers.Therefore,theirmodeofactivationmustalsobeunique.NowineLife,DanielLeahyattheJohnsHopkinsUniversitySchoolofMedicinea
5、ndcol-leaguesreportnewinsightsintohowtheinsulinhehormoneinsulinandtherelatedgrowthandIGF1receptorsareactivated(Kavranetal.,TfactorIGF1(shortforinsulin-likegrowth2014).factor-1)regulatethestorageoffatsandLeahyandco-workers—whoincludeJennifercarbohydrates,growthanddevelopment,andKavr
6、anasthefirstauthorandothersatJohnsmanyotherimportantprocessesinhumanphys-HopkinsandDEShawResearch—havebuiltoniology(Nakaeetal.,2001;DeMeyts,2004;previousstructuralworkontheinsulinreceptor.TheSiddle,2012).Nevertheless,preciselyhowthesecrystalstructureoftheentireextracellularregionof
7、smallproteinsactivatetheirreceptorsisstilltheinsulinreceptorwasdeterminedintheabsencesomethingofamystery.ofinsulinaboutadecadeago(McKernetal.,ThereceptorsforinsulinandIGF1aremem-2006),whileastructureofafragmentoftheextra-bersofthebroadfamilyofreceptortyrosinecellularregionthatinclu
8、dedboundinsulinwaspub-kina
