Dynamic Conformational Changes in MUNC18 Prevent Syntaxin Binding 英文参考文献.docVIP

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Dynamic Conformational Changes in MUNC18 Prevent Syntaxin Binding 英文参考文献.doc

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Dynamic Conformational Changes in MUNC18 Prevent Syntaxin Binding 英文参考文献

DynamicConformationalChangesinMUNC18Prevent SyntaxinBinding DanaBar-On1,2,EstherNachliel2,MenachemGutman2,UriAshery1* 1DepartmentofNeurobiology,TelAvivUniversity,TelAviv,Israel,2LaserLaboratoryforFastReactionsinBiology,DepartmentofBiochemistry,GeorgeS.WiseFacultyof LifeSciences,TelAvivUniversity,TelAviv,Israel Abstract The Sec1/munc18 protein family is essential for vesicle fusion in eukaryotic cells via binding to SNARE proteins. Protein kinase C modulates these interactions by phosphorylating munc18a thereby reducing its affinity to one of the central SNAREmembers, syntaxin-1a.Theestablished hypothesisis thatthereducedaffinity ofthephosphorylated munc18ato syntaxin-1aisaresultoflocalelectrostaticrepulsionbetweenthetwoproteins,whichinterfereswiththeircompatibility. Thecurrentstudychallengesthisparadigmandoffersanovelmechanisticexplanationbyrevealingasyntaxin-non-binding conformation of munc18a that is induced by the phosphomimetic mutations. In the present study, using molecular dynamicssimulations,weexploredthedynamicsofthewild-typemunc18aversusphosphomimeticmutantmunc18a.We focusedonthestructuralchangesthatoccurinthecavitybetweendomains3aand1,whichservesasthemainsyntaxin- binding site. The results of the simulations suggest that the free wild-type munc18a exhibits a dynamic equilibrium betweenseveralconformationsdifferinginthesizeofitscavity(themainsyntaxin-bindingsite).Theflexibilityofthecavity’s sizemightfacilitatethebindingorunbindingofsyntaxin.Insilicoinsertionofphosphomimeticmutationsintothemunc18a structure induces the formation of a conformation where the syntaxin-binding area is rigid and blocked as a result of interactionsbetweenresidueslocatedonbothsidesofthecavity.Therefore,wesuggestthatthereducedaffinityofthe phosphomimetic mutant/phosphorylated munc18a is a result of the closed-cavity conformation, which makes syntaxin binding energetically and sterically unfavorable. The current study demonstrates the potential of phosphoryalation, an essential