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A Dynamic View of Domain-Motif Interactions 英文参考文献
ADynamicViewofDomain-MotifInteractions
EyalAkiva¤a,GilgiFriedlander¤b,ZoharItzhaki¤c,HanahMargalit*
DepartmentofMicrobiologyandMolecularGenetics,IMRIC,FacultyofMedicine,TheHebrewUniversityofJerusalem,Jerusalem,Israel
Abstract
Manyprotein-proteininteractionsaremediatedbydomain-motifinteraction,whereadomaininoneproteinbindsashort
linearmotifinitsinteractingpartner.Suchinteractionsareofteninvolvedinkeycellularprocesses,necessitatingtheirtight
regulation.Acommonstrategyofthecelltocontrolproteinfunctionandinteractionisbypost-translationalmodifications
of specific residues, especially phosphorylation. Indeed, there are motifs, such as SH2-binding motifs, in which motif
phosphorylation is required for the domain-motif interaction. On the contrary, there are other examples where motif
phosphorylationpreventsthedomain-motifinteraction.Herewepresentalarge-scaleintegrativeanalysisofexperimental
humandataofdomain-motifinteractionsandphosphorylationevents,demonstratinganintriguingcouplingbetweenthe
two.WereportsuchcouplingforSH3,PDZ,SH2andWWdomains,whereresiduephosphorylationwithinornexttothe
motifisimpliedtobeassociatedwithswitchingonoroffdomainbinding.Fordomainsthatrequiremotifphosphorylation
for binding, such as SH2 domains, we found coupled phosphorylation events other than the ones required for domain
binding.Furthermore,weshowthatphosphorylationmightfunctionasadoubleswitch,concurrentlyenablinginteraction
ofthemotifwithonedomainanddisablinginteractionwithanotherdomain.Evolutionaryanalysisshowsthatco-evolution
of the motif and the proximal residues capable of phosphorylation predominates over other evolutionary scenarios, in
whichthemotifappearedbeforethepotentiallyphosphorylatedresidue,orviceversa.Ourfindingsprovidestrengthening
evidenceforcoupledinteraction-regulationunits,definedbyadomain-bindingmotifandaphosphorylatedresidue.
Citation: Akiva E, Friedlander G, Itzhaki Z, Margalit H (2012) A Dynamic View of Domain-Motif Interactions. PLoS Comput Biol 8(1): e1002341. doi:
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