-水分子通道蛋白的结构与功能

瑞典皇家科学院在2003年10月8日宣布,当年的诺贝尔化学奖颁发给在水通道和离子通道的基础研究中分别做出突出贡献的PeterAgre和RoderickMackin-non,同时指出:In2000and2001,thefirsthigh-resolution3DstructuresofAQP1andare-latedglycero-lselectivebacterialchannelprotein(GlpF)werereported(Fuetal.,2000;Mu-rataetal.,2000;Renetal.,2001;Suietal.,2001).Basedonthesestructures,detailedmodelshavebeenputforwardtoexplainthehighpermeationrate,thestrictwaterselectivity,andtheabilityofAQP1topreventprotonleakage()(引自瑞典皇家科学院在2003年10月8日发布的Advancedinformation)在上述引文的第一作者中,Murata是与P.Agre等一道发表论文的日本科学家,其它三位都是中国青年学者:富大雄(Fu,D.),任罡(Ren,G.)和隋海心(Sui,H.),他们的论文出处见本文的参考文献[33][31]和[32]本文作者隋海心是大连理工大学材料工程系的研究生(19891995)任罡是北京科技大学材料物理系的研究生(19931997)他们都师从郭可信院士,在中国科学院北京电子显微镜实验室从事电子显微像的图像处理与三维重构的博士论文工作隋海心在博士毕业后还在1996年从国家自然科学基金委员会申请到题为电子晶体学图像处理在准晶近似相结构研究中的应用的资助任罡在彭练矛研究员的具体指导下的博士论文题目是定量电子显微学及其应用他们在国内已有扎实的电子显微学和晶体学基础,在去美转攻蛋白膜水通道的研究工作后,很快作出优异成绩,引起世人注意:20041*e-mail:[e-mail];[e-mail]水分子通道蛋白的结构与功能隋海心*(LifeSciencesDivision,LawrenceBerkeleyNationalLaboratory,Berkeley,CA94720,USA)任罡*(DepartmentofCellBiology,TheScrippsResearchInstitute,LaJolla,CA92037,USA)水分子穿越双磷脂生物膜的输运机理是生理学和细胞生物学中一个长期未能解决的重要问题AQP1水通道蛋白的发现和鉴定使得人们确认出一个新的蛋白质家族水通道蛋白家族正是这一蛋白家族的存在,使得水分子可以进行快速的跨膜传输由晶体学方法解出的哺乳动物AQP1水通道蛋白的原子结构,最终揭示了水通道蛋白只允许水分子快速传输而阻挡其他的小分子和离子(包括质子H+)的筛选输运机理本文概述了水通道蛋白的发现和其对水分子的筛选传输机理水通道蛋白水传输结构与功能膜通道:Q51:A:1005-281X(2004)02-0145-0816220043化学进展PROGRESSINCHEMISTRYVol.16No.2Mar.,2004StructureandMechanismofWaterChannelsSuiHaixin*(LifeSciencesDivision,LawrenceBerkeleyNationalLaboratory,Berkeley,CA94720,USA)RenGang*(DepartmentofCellBiology,TheScrippsResearchInstitute,LaJolla,CA92037,USA)AbstractThemechanismofwatertransportacrossbiologicalmembraneshasbeenalongstandingprobleminphys-iologyandcellbiology.ThediscoveryandcharacterizationoftheAQP1waterchannelproteinleadstotheidentificationoftheaquaporinfamilyofwaterchannelswhichisresponsibleforthewaterpermeabilityofbiologicalmembranes.Theatom-icstructureofmammalianAQP1revealshowthisfamilyofproteinstransportswatermolecules,butnotothersmallmole-culesandions(includingprotons),rapidlyacrosscellmembranes.Thisreviewsummarizesthediscoveryofwaterchan-nelproteinsandtheirmechanismofwater-specifictransport.Keywordsaquaporin;watertransport;structureandfunction;membranechannel***,C12112,kDa,,,70%,,(aquaporin,AQP)AQP130[1],,,,,19,(channel)205080,[27]MaceyFarmer1970[4],pCMBS[810],80,JohnHopkinsPeterAgreRh32kDa**28kDaRhAgre1988[11],146化学进展16CHIP28(channe-llikeintegralmembraneprotein,28kDa)[12]CHIP28,AgreCHIP28mR-NA(xenopusoocytes),,CHIP28,CHIP28(1)[8]CHIP281:aquaporin1AQP1[13]1AQP1mRNA();,AQP1mRNA()[8](PeterAgre)Fig.1XenopusoocytesmicroinjectedwithAQP1mRNAsweldrapidlywhenplacedinahypo-osmoticmedium(thefirstrowoftheimages),incontrasttononinject-edoocytes(thesecondrowoftheimages)(ThefigurewasreprintedwithpermissionfromProf.PeterAgre)*(),,AQP1,10,:AQP0AQP9[1417]AQP,(MIP:majorintrinsicprotein)AQP1,350,([1],[18])[19],,AQP(glycerolfacilitators)[18,19][20,21],,,()AQP1*,XX,,,,,[2325]RichardHenderson[22,23],,[26],AQP1,AQP1LawrenceBerkeley,Scripps,JohnHopkinsPeterAgre1997147268[2729]20002001,PeterAgreFu-jiyoshiScripps3837AQP1[30,31]BerkeleyX22AQP1,[32],XGlpF(GlycerolfacilitatorinE.co-li)(22)[33]RockefellerRoderickMacKinnonDoyleKcsA[34]*GlpFKcsAAQP1,[32]*RoderickMacKinnon2003AQP1(2)(AQP1),6,(3)2,4AQP1([35],)Fig.2ProjectiondensitymapofAQP1waterchannelprotein.ThefunctionalunitofAQP1isatetramerwitheachmonomerprovidinganindependentchannelporethattransportswateracrosscellmembrane(ThefigurewasmodifiedfromtheFigure1cinreference[35])3AQP16,([36]11)Fig.3ArchitectureofhelicesinanAQP1monomer.Eachmonomercontainssixtransmembranehelicespackedto-gethertolikeastick-bundle.Thenon-membrane-span-ninghelices,positionedend-to-end,defineamajorportionofthewatertransportationporerunningthroughthecenterofthebundle.(ThefigurewasmodifiedfromFigure11ofreference[36])Asn-Pro-Ala(NPA),,,,KcsA(6(b)),2064,148化学进展16(6(a))4,4AQP18,His182(H182),Arg197(R197),Phe58(F58)Cys191(C191)44(6(a))([32]24,MOSCRIPT[37]RAS-TER3D[38])Fig.4Structureofthewaterchannelandlocationsoftrappedwatermolecules.Thestructuralbackboneisinribbonformat.Theporeprofileishighlightedbyanarrayofbluedots.Theconstrictionregion,formedbyHis182,Arg197,Phe58andCys191,isvisibleasthepinched-inareaintheextracellularhalfoftheprofilewhichisabout8abovethemiddle.Fourwatermoleculestrappedinsidethechannelporearedepictedasgreenspheres.Therelativelyhydrophilicenvironmentaroundthewaterbindingpositionswasprovidedmainlybytheaminoacidresiduesfromthetwoloopsextendingfromofthenon-membrane-spanninghelices(ThisfigurewasproducedusingMOLSCRIPT[36]andRaster3D[37]basedonFigures2and4fromreference[32]),,,4,NPA,8His182,Arg197,Phe58Cys19144AQP128,Z,4,AQP122[39],444,Asn194Asn78,His764,,,AQP1,AQP1(1)AQP1His182,Arg197,Phe58Cys191428,,,4,,AQP1GlpF[33],4Gly191,Arg206,Trp48Phe200(5)GlpFAQP1,GlpF14925AQP1GlpFAQP1(H182,R197,F58,C191),GlpF(G191,R206,W48,F200),AQP1GlpF,([32]5,)Fig.5Acomparisonoftheresiduesdefiningtheconstrictionre-gionofAQP1andGlpF.Residuesinvolvedinthefor-mationoftheAQP1constrictionregion(H182,R197,F58andC191)aredepictedi