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1、5266Biochemistry2008,47,5266–5270†ZebrafishNeuroglobinIsaCell-Membrane-PenetratingGlobin‡,‡,§SeijiWatanabeandKeisukeWakasugi*DepartmentofLifeSciences,GraduateSchoolofArtsandSciences,TheUniVersityofTokyo,3-8-1Komaba,Meguro-ku,Tokyo153-8902,Japan,andPrecursoryResearc
2、hforEmbryonicScienceandTechnology(PRESTO),JapanScienceandTechnology(JST),4-1-8Honcho,Kawaguchi,Saitama332-0012,JapanReceiVedFebruary18,2008;ReVisedManuscriptReceiVedMarch26,2008ABSTRACT:Neuroglobin(Ngb)isarecentlydiscoveredvertebratehemeproteinthatisexpressedinthe
3、brainandcanreversiblybindoxygen.MammalianNgbisinvolvedinneuroprotectionunderoxidativestressconditions,suchasischemiaandreperfusion.WepreviouslydemonstratedthathumanferricNgbbindstotheRsubunitofheterotrimericGproteins(GRi)andactsasaguaninenucleotidedissociationinhi
4、bitor(GDI)forGRi.Recently,weusedaproteindeliveryreagent,Chariot,anddemonstratedthattheGDIactivityofhumanNgbistightlycorrelatedwithitsneuroprotectiveactivity.Inthepresentstudy,wefoundthatchimericZHHHNgb,inwhichmoduleM1ofhumanNgbisreplacedbythatofzebrafishNgb,protect
5、sPC12cellsagainstoxidativestress-inducedcelldeathevenintheabsenceofChariot.Usingfluoresceinisothiocyanate(FITC)-labeledNgbproteins,wedemonstratedthatbothzebrafishandchimericZHHHNgbcanpenetratecellmembranesintheabsenceofChariot,suggestingthatmoduleM1ofzebrafishNgbcant
6、ranslocateintocells.Thisisthefirstreportofanativecell-membrane-penetratingglobin.1Neuroglobin(Ngb)isahemeprotein,recentlydiscoveredGDIactivity(14).Thesefindingsledustoproposethatinthemammalianbrain,whichcanreversiblybindoxygenhumanNgbmaybeanoveloxidativestress-respo
7、nsive(O2)(1-3).MammalianNgbiswidelyexpressedinthesensorforsignaltransductioninthebrain(14,15).Recently,cerebralcortex,hippocampus,thalamus,hypothalamus,wedemonstratedthathumanNgbcompeteswithγsubunitscerebellum,andretina(1,4-8).Itwasrecentlysuggestedofheterotrimer
8、icGprotein(Gγ)forbindingtoGRi,thatmammalianNgbmightbeinvolvedintheneuronalsuggestingthattheinteractionofGDP-boundGRiwithferricresponsetohypoxiaandische
