Structural basis for recognition of the third SH3 domain of full‐length R85 (R85FL)/ponsin by ataxin‐7

摘要

Ataxin‐7(Atx7)isacomponentofthenucleartranscriptionco‐activatorcomplex;itspolyglutamine(polyQ)expansionmaycausenuclearaccumulationandrecruitnumerousproteinstotheintranuclearinclusionbodies.Full‐lengthR85(R85FL)issuchaproteinsequesteredbypolyQ‐expandedAtx7.Here,wereportthatAtx7specificallyinteractswiththethirdSH3domain(SH3C)ofR85FLthroughitssecondportionofproline‐richregion(PRR).NMRstructuralanalysisoftheSH3CdomainanditscomplexwithPRRrevealedthatSH3CcontainsalargenegativelychargedsurfaceforbindingwiththeRRTRmotifofAtx7.MicroscopyimagingdemonstratedthatsequestrationofR85FLbythepolyQ‐expandedAtx7incellismediatedbythisspecificSH3C–PRRinteraction,whichisimplicatedinthepathogenesisofspinocerebellarataxia7...