Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis 英文参考文献.docVIP

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Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis 英文参考文献.doc

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Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis 英文参考文献

BlockadeoftheBAKHydrophobicGroovebyInhibitory PhosphorylationRegulatesCommitmenttoApoptosis AbulAzad,JoannaFox,SabrinaLeverrier¤,AlanStorey* DepartmentofOncology,WeatherallInstituteofMolecularMedicine,UniversityofOxford,JohnRadcliffeHospital,Oxford,UnitedKingdom Abstract The BCL-2 family protein BAK is a key regulator of mitochondrial apoptosis. BAK activation first involves N-terminal conformationalchangesthatleadtothetransientexposureoftheBAKBH3domainthattheninsertsintoahydrophobic grooveonanotherBAKmoleculetoformsymmetricdimers.Weshowedrecentlythatpost-translationalmodificationsare important in the regulation of BAK conformational change and multimerization, with dephosphorylation at tyrosine 108 constitutinganinitialstepintheBAKactivationprocess.Wenowshowthatdephosphorylationofserine117(S117),located intheBAKhydrophobicgroove,isalsocriticalforBAKactivationtoproceedtocompletion.PhosphorylationofBAKatS117 hastwoimportantregulatoryfunctions:first,itoccludesthebindingofBH3-containingpeptidesthatbindtoBAKcausing activationandcytochromecreleasefrommitochondria;second,itpreventsBAK-BH3:BAK-Grooveinteractionsthatnucleate dimerformationforsubsequentmultimerization.Hence,BH3-mediatedBAKconformationalchangeandsubsequentBAK multimerizationforcytochromecreleaseandcelldeathisintimatelylinkedto,anddependenton,dephosphorylationat S117. Our study reveals important novel mechanistic and structural insights into the temporal sequence of events governingtheprocessofBAKactivationincommitmenttocelldeathandhowtheyareregulated. Citation: Azad A, Fox J, Leverrier S, Storey A (2012) Blockade of the BAK Hydrophobic Groove by Inhibitory Phosphorylation Regulates Commitment to Apoptosis.PLoSONE7(11):e49601.doi:10.1371/journal.pone.0049601 Editor:BorisZhivotovsky,KarolinskaInstitutet,Sweden ReceivedMarch21,2012;AcceptedOctober15,2012;PublishedNovember26,2012 Copyright: ? 2012 Azad et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License,