Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis 英文参考文献.docVIP

DynamicAllosteryintheMethionineRepressorRevealed byForceDistributionAnalysis WolframStacklies1,3,FeiXia1,FraukeGra¨ter1,2,3* 1CAS-MPGPartnerInstituteforComputationalBiology,KeylaboratoryofComputationalBiology,ChineseAcademyofSciences,Shanghai,China,2Max-Planck-Institute forMetalsResearch,Stuttgart,Germany,3BioquantBQ0031,HeidelbergUniversity,Heidelberg,Germany Abstract Many fundamental cellular processes such as gene expression are tightly regulated by protein allostery. Allosteric signal propagationfromtheregulatorytotheactivesiterequireslong-rangecommunication,themolecularmechanismofwhich remainsamatterofdebate.Aclassicalexampleforlong-rangeallosteryistheactivationofthemethioninerepressorMetJ,a transcription factor. Binding of its co-repressor SAM increases its affinity for DNA several-fold, but has no visible conformational effect on its DNA binding interface. Our molecular dynamics simulations indicate correlated domain motions within MetJ, and quenching of these dynamics upon SAM binding entropically favors DNA binding. From monitoringconformational fluctuationsalone,itis notobvioushowthepresenceof SAMis communicatedthrough the largely rigid core of MetJ and how SAM thereby is able to regulate MetJ dynamics. We here directly monitored the propagationofinternalforcesthroughtheMetJstructure,insteadofrelyingonconformationalchangesasconventionally done.Ourforcedistribution analysissuccessfullyrevealedthemolecularnetwork forstrainpropagation,whichconnects collectivedomainmotionsthroughtheproteincore.PartsofthenetworkaredirectlyaffectedbySAMbinding,givingrise totheobservedquenchingoffluctuations.Ourresultsareingoodagreementwithexperimentaldata.Theforcedistribution analysissuggestsitselfasavaluabletooltogaininsightintothemolecularfunctionofawholeclassofallostericproteins. Citation: Stacklies W,Xia F,Gra¨ter F(2009)Dynamic Allostery intheMethionineRepressorRevealedbyForceDistribution Analysis. PLoSComput Biol5(11): e1000574.doi:10.1371/journal.pcbi.100057