Amyloidogenic Regions and Interaction Surfaces Overlap in Globular Proteins Related to Conformational Diseases 英文参考文献.docVIP

AmyloidogenicRegionsandInteractionSurfacesOverlap inGlobularProteinsRelatedtoConformationalDiseases VirginiaCastillo,SalvadorVentura* DepartamentdeBioqu?′micaiBiologiaMolecularandInstitutdeBiotecnologiaideBiomedicina,UniversitatAuto`nomadeBarcelona,Barcelona,Spain Abstract Proteinaggregationunderliesawiderangeofhumandisorders.Thepolypeptidesinvolvedinthesepathologiesmightbe intrinsicallyunstructuredordisplayadefined3D-structure.Littleisknownabouthowglobularproteinsaggregateintotoxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however,alwaysinitiatedbytheestablishmentofanomalousprotein-proteininteractions.Therefore,inthepresentwork, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteinsassociatedwithconformationaldiseases.Computationalanalysisofthenativecomplexesformedbytheseproteins showsthataggregation-proneregionsdofrequentlyoverlapwithproteininterfaces.Thespatialcoincidenceofinteraction sitesandaggregatingregionssuggeststhattheformationoffunctionalcomplexesandtheaggregationoftheirindividual subunitsmightcompeteinthecell.Accordingly,singlemutationsaffectingcomplexinterfaceorstabilityusuallyresultin theformationoftoxicaggregates.Itissuggestedthatthestabilizationofexistinginterfacesinmultimericproteinsorthe formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregationofglobularproteins. Citation:CastilloV,VenturaS(2009)AmyloidogenicRegionsandInteractionSurfacesOverlapinGlobularProteinsRelatedtoConformationalDiseases.PLoS ComputBiol5(8):e1000476.doi:10.1371/journal.pcbi.1000476 Editor:RuthNussinov,NationalCancerInstitute,UnitedStatesofAmericaandTelAvivUniversity,Israel ReceivedMarch4,2009;AcceptedJuly20,2009;PublishedAugust21,2009 Copyright: ?2009Castillo, Ventura.Thisisanopen-accessarticle distributedunderthetermsoftheCreative Commons AttributionLicense