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1、ExonucleaseTREX1degradesdouble-strandedDNAtopreventspontaneouslupus-likeinflammatorydiseasea,1a,1aba,c,2a,c,2JessicaL.Grieves,JasonM.Fye,ScottHarvey,JasonM.Grayson,ThomasHollis,andFredW.PerrinoabcDepartmentofBiochemistry,DepartmentofMicrobiologyandImmunology,andCe
2、nterforStructuralBiology,WakeForestSchoolofMedicine,Winston-Salem,NC27157EditedbyJamesM.Berger,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,andapprovedMarch12,2015(receivedforreviewDecember16,2014)TheTREX1geneencodesapotentDNAexonuclease,andmu-TREX1catalyti
3、cfunctiondependsonthedimericstructure,withtationsinTREX1causeaspectrumoflupus-likeautoimmunedis-residuesfromoneprotomercontributingtoDNAbindingandeases.Mostlupuspatientsdevelopautoantibodiestodouble-degradationintheopposingprotomer(21,22).SomeTREX1strandedDNA(dsDN
4、A),butthesourceofDNAantigenisdisease-causingmutantsexhibitcompletelossofcatalyticfunction,unknown.TheTREX1D18Nmutationcausesamonogenic,cutaneouswhereasothersexhibitalteredcellularlocalization(8,10).Asubsetformoflupuscalledfamilialchilblainlupus,andtheTREX1D18NofTR
5、EX1catalyticmutantsataminoacidpositionsAsp-18andenzymeexhibitsdysfunctionaldsDNA-degradingactivity,provid-Asp-200exhibitselectivelydysfunctionalactivitiesondsDNA.ingalinkbetweendsDNAdegradationandnucleicacid-mediatedThesemutationscauseautosomal-dominantdiseasebyre
6、tainingautoimmunedisease.WedeterminedthestructureoftheTREX1DNA-bindingproficiencyandblockingaccesstoDNA3′terminiD18NproteinincomplexwithdsDNA,revealinghowthisexonu-fordegradationbyTREX1WTenzyme(21,23,24).TheTREX1cleaseusesanovelDNA-unwindingmechanismtoseparatethec
7、atalyticsitesaccommodatefournucleotidesofssDNA,andad-polynucleotidestrandsforsingle-strandedDNA(ssDNA)loadingditionalstructuralelementsarepositionedadjacenttotheactiveintotheactivesite.TheTREX1D18NdsDNAinteractionscoupledsitesforpotentialDNApolynucleotideinteracti
8、ons.withcatalyticdeficiencyexplainhowthismutantnucleasepre-TheconnectionbetweenfailuretodegradeDNAbyTREX1ventsdsDNAdegradation.WetestedtheeffectsofTREX1
