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Proteases Gleaned from Investigations of Isolated Domains Slicing A Downloaded from www.proteinscience.org on August 3, 2006 Slicing a protease: Structural features of the ATP-dependent Lon proteases gleaned from investigations of isolated domains Tatyana V. Rotanova, Istvan Botos, Edward E. Melnikov, Fatima Rasulova, Alla Gustchina, Michael R. Maurizi and Alexander Wlodawer Protein Sci. 2006 15: 1815-1828 Access the most recent version at doi:10.1110/ps.052069306 References This article cites 97 articles, 26 of which can be accessed free at: http://www.proteinscience.org/cgi/content/full/15/8/1815#References Email alerting Receive free email alerts when new articles cite this article - sign up in the box at the service top right corner of the article or click here Notes To subscribe to Protein Science go to: http://www.proteinscience.org/subscriptions/ © 2006 Cold Spring Harbor Laboratory Press JOBNAME: PROSCI 15#8 2006 PAGE: 1OUTPUT: Tuesday July 11 00:18:18 2006 csh/PROSCI/118158/ps0520693 Downloaded from www.proteinscience.org on August 3, 2006 REVIEW Slicing aprotease: Structural features of the ATP-dependent Lon proteases gleaned from investigations of isolated domains TATYANAV.ROTANOVA, 1 ISTVAN BOTOS, 2,3 EDWARD E. MELNIKOV, 1 FATIMA RASULOVA, 4,5 ALLA GUSTCHINA,2 MICHAEL R. MAURIZI,4 2 AND ALEXANDER WLODAWER 1 Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry,Russian Academy of Sciences, Moscow117997, Russia 2 Macromolecular Crystallography Laboratory,National Cancer Institute at Frederick, Frederick, Maryland 21702, USA 3 Laboratory of Molecular Biology,National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA 4 Laboratory of Cell Biology,National Cancer Institute, Bethesda, Maryland 20892, USA 5 Enteric Diseases Department, Infectious Diseases Directorate, Naval Medical Research Center,SilverSpring, Maryland 20910, USA Abstract ATP-DEpendentLon proteasesare multi-domain enzymesfound in alllivingorganisms.All Lonproteases containanATPasEDomainbelonging to theAAA+ superfamilyofmolecularmachinesand aproteolytic domain with aserine-lysine catalyticdyad. Lonproteases canbEDividED into twosubfamilies,LonAand LonB,exemplifiED by thE Escherichiacoli anD Archaeoglobusfulgidus paralogs,respectively. TheLonA subfamily is DEfinedbythe presence of alarge N-terminal domain,wh ereasthe LonB subfamilyhas no such domain,but hasamembrane-spanningdomainthatanchors theprot eintothe cytoplasmicsideofthe membrane.The twosubfamilies also differ in theirconsensus sequences. Recent crystalstructuresfor several individual domainsand sub-fragmentsofLon proteaseshavebegun to illuminate similarities anDDifferences in structure–function relationshipsbetween thetwo subfamilies. Differencesinorientation of theactivesitE residues in severalisolatedLon protease domainspoint to possible rolesfor theAAA+ domainsand/or substrates in positioningthe catalyticresidueswithin theactivesite. Structures of theproteolytic domains have also indicatedapossible hexamericarrangement of subunits in thenativestate of bacterialLon proteases. Thestructure of alarge segmentofthe N-terminal domain hasrevealedafoldingmotif present in otherprotein families of unknownfunctionand should lead to newinsightsregarding ways in whichLon interactswith substrates or othercellularfactors.These firstglimpsesofthe structureofLon areheraldingan exciting newera of research on this ancientfamilyofproteases. Keywords: AAA + protein; Lon protease; ATP-dependent protease; Ser-Lys dyad; LonA and LonB subfamilies; domains; crystal structure The Lon family of peptidases Reprintrequeststo: Alexander Wlodawer,Macromolecular Crystal- lography Laboratory,NCI at Frederick, P.O. BoxB,Frederick,MD The Lonprotease family (MEROPS [Rawlings et al. 21702, USA; e-mail:[email protected]; fax: (301) 846-6322;or TatyanaV.Rotanova,Shemyakin–OvchinnikovInstitute of Bioorganic 2004] clan SJ,family S16),which is conservED in thE Chemistry,Russian Academy of Sciences,Miklukho-Maklayast. 16/10, prokaryotes andineukaryoticorganelles such as mito- GSP-7, Moscow 117997, Russia; e-mail: [email protected]; fax: +7-495-3357103; or Michael R. Maurizi, LaboratoryofCell chondria and peroxisomes, is themostwidespread family Biology,NationalCancer Institute, Bethesda, MD 20892, USA; e-mail: of ATP-dependent proteases. Prokaryotic Lons are key [email protected];fax:(301) 480-2284. Article and publication are at http://www.proteinscience.org/cgi/doi/ enzymes responsible for intracellularproteolysis, con- 10.1110/ps.052069306. tributing to protein quality and cellular homeostasis by Protein Science (2006), 15:1815–1828. Published by Cold Spring Harbor Laboratory Press. Copyright Ó 2006 The Protein Society 1815 ps0520693 Rotanova et al. REVIEW RA JOBNAME: PROSCI 15#8 2006 PAGE: 2OUTPUT: Tuesday July 11 00:18:19 2006 csh/PROSCI/118158/ps0520693 Downloaded from www.proteinscience.org on August 3, 2006 Rotanova et al. eliminating mutant andabnormalproteins andparticipat- Lons are diviDEdinto twosubfamilies, LonA and inginrapid turnoverofselect short-livedregulatory LonB,basED on differencesinthe number of domains proteins(Goldberg1992;Gottesman and Maurizi 1992; and characteristic sequences within the domains (Rota- Gottesman 1996;Wickner et al.1999). Though less well nova et al.2003, 2004). Both subfamilies contain the studied,eukaryotic Lons have been shown to exhibit ATPase (A) domains that include typical AAA + modules, similarly important regulatory and protein quality control as well as theproteolytic (P) domains, butwhereas LonA functions in mitochondria (Van Dycket al.1994; vanDijl enzymes contain alarge N-terminal(N) domain, the et al. 1998;Botaand Davies 2002). Lon,like allother LonB enzymeshavenoN-domain buthavealarge ATP-dependent proteases (FtsH, ClpAP,ClpXP,HslVU, transmembrane domain insertion within the AAA + mod- andthe 26 Sproteasome), belongstothe AAA+ protein ule betwEEnthe Walker motifs Aand B(Fig. 1).Ithad superfamily (ATPases associatED with diverse cellular been suggestedthat Lons are serine proteases(Chungand activities) (Neuwald et al. 1999;Maurizi and Li 2001; Goldberg1981;Waxman andGoldberg1982; Goldberg Oguraand Wilkinson 2001; Lupas andMartin 2002;Iyer et al. 1994), althoughthe amino acid sequencesofLonA et al. 2004). In additiontoprotein unfoldingand pro- andLonBP-domainsshownohomologywith serine teolysis, AAA + proteinsare involvED in many cellular proteasescontaining the classicalcatalytictriad Ser- processes, including membrane fusion, protein andor- His-Asp(Amerik et al.1988, 1990,1991; Goldberg et al. ganelle translocation, DNAand RNAunwinding, assem- 1994; Rotanovaetal. 2004), or,indeed, to any other bly anDDisassembly of multi-protein complexes, anD proteases. Active-site-directed inhibitors of classical serine microtubulesevering,toname thebestknown. The proteases, such as sulfonyl fluorides, chloromethyl ketones, cellular activity of AAA+ proteins is largely DEfinedby or fluorophosphates, are poor inhibitors of Lon, and nonE the functional partners with which theyassociate. In thE has been shown to modify the active site residues. Com- case of Lon, theAAA+ domainiscovalently fusedto parative analysisofthe primary structuresofthe Lonpool aproteasEDomain. and site-directed mutagenesis of the full-length Escherichia Lonproteases function as oligomeric assemblies, coli Lon(EcLon) (Rotanovaetal. 2003, 2004), along with whichhad been variouslyreportedtoconsist of four to the recently DEtermined structure of the EcLonP-domain eight identical subunits (Goldbergetal. 1994;Roudiak (Botosetal. 2004b), establishED that the activesites of Lon et al. 1998; Lee et al.2004). Anumber of direct anD proteases haveaSer-Lys catalytic dyad (Ser679 and Lys722 indirect observations indicate that bacterial Lons form in the EcLon numbering). ringsconsisting of six subunits(LeEEtal. 2004; Park ThEDomainsin EcLon,arepresentative member of the et al. 2006). The yeast mitochondrial Lon has been shown LonA subfamily,are assignED by us for thepurpose of to form seven-memberED rings(Stahlbergetal. 1999), anD this review as 1–309(N-domain), 310–584 (A-domain), similararrangementsmight also be presentinproteinsfrom and 585–784 (P-domain), althoughthere is no consensus othersources.The subunits themselves arecomposedof on such adivision at this time andthe exactposition threeormoreindepenDEntly foldED domains(seebelow). of domain boundaries, especiallybetween the N- anD Figure1. Schematic diagram of the typical members of LonA and LonB subfamilies, represented by E. coli and A. fulgidus Lon proteases, respectively.Domain definitions are explained in the text.(Dark blue) The segments for which three-dimensional structures have been solved; (green) the locations of the Walker Aand Bmotifs (AAA+ module), marked Aand B; (red and orange) residues forming acatalytic dyad (serine [S] and lysine [K]); (yellow) the transmembrane domain of the LonB proteases; (magenta) the sensor-1 and sensor-2 regions. The positions of putative intein insertions located just after the TM domains in some LonB proteases (but not in AfLonB) are not shown. 1816 Protein Science, vol. 15 Fig. 1live 4/C JOBNAME: PROSCI 15#8 2006 PAGE: 3OUTPUT: Tuesday July 11 00:18:31 2006 csh/PROSCI/118158/ps0520693 Downloaded from www.proteinscience.org on August 3, 2006 Structural featuresofLon proteases A-domains, may be subject to future revision. AAA+ with different substrates,reflecting size, global andlocal modules generally contributetotargetselection anD thermodynamicstability,and interactions of unfoldED regulation of the activity of the associated functional
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