Key points are not available for this paper at this time.
Small ubiquitin-like modifier (SUMO) proteases regulate the abundance and lifetime of SUMO-conjugated substrates by antagonizing reactions catalyzed by SUMO-conjugating enzymes. Six SUMO proteases constitute the human SENP/ULP protease family (SENP1-3 and SENP5-7). SENP6 and SENP7 include the most divergent class of SUMO proteases, which also includes the yeast enzyme ULP2. We present the crystal structure of the SENP7 catalytic domain at a resolution of 2.4Å. Comparison with structures of human SENP1 and SENP2 reveals unique elements that differ from previously characterized structures of SUMO-deconjugating enzymes. Biochemical assays show that SENP6 and SENP7 prefer SUMO2 or SUMO3 in deconjugation reactions with rates comparable with those catalyzed by SENP2, particularly during cleavage of di-SUMO2, di-SUMO3, and poly-SUMO chains composed of SUMO2 or SUMO3. In contrast, SENP6 and SENP7 exhibit lower rates for processing pre-SUMO1, pre-SUMO2, or pre-SUMO3 in comparison with SENP2. Structure-guided mutational analysis reveals elements unique to the SENP6 and SENP7 subclass of SENP/ULP proteases that contribute to protease function during deconjugation of poly-SUMO chains. Small ubiquitin-like modifier (SUMO) proteases regulate the abundance and lifetime of SUMO-conjugated substrates by antagonizing reactions catalyzed by SUMO-conjugating enzymes. Six SUMO proteases constitute the human SENP/ULP protease family (SENP1-3 and SENP5-7). SENP6 and SENP7 include the most divergent class of SUMO proteases, which also includes the yeast enzyme ULP2. We present the crystal structure of the SENP7 catalytic domain at a resolution of 2.4Å. Comparison with structures of human SENP1 and SENP2 reveals unique elements that differ from previously characterized structures of SUMO-deconjugating enzymes. Biochemical assays show that SENP6 and SENP7 prefer SUMO2 or SUMO3 in deconjugation reactions with rates comparable with those catalyzed by SENP2, particularly during cleavage of di-SUMO2, di-SUMO3, and poly-SUMO chains composed of SUMO2 or SUMO3. In contrast, SENP6 and SENP7 exhibit lower rates for processing pre-SUMO1, pre-SUMO2, or pre-SUMO3 in comparison with SENP2. Structure-guided mutational analysis reveals elements unique to the SENP6 and SENP7 subclass of SENP/ULP proteases that contribute to protease function during deconjugation of poly-SUMO chains. Ubiquitin (Ub) 3The abbreviations used are: Ub, ubiquitin; Ubl, Ub-like; r.m.s.d., root mean square deviation; SUMO, small ubiquitin-like modifier; PDB, Protein Data Bank. and ubiquitin-like (Ubl) proteins are conjugated to target proteins via an isopeptide bond between the Ub/Ubl C-terminal residue and a lysine residue on the protein target (1Hershko A. Ciechanover A. Annu. Rev. Biochem. 1998; 67: 425-479Crossref PubMed Scopus (6907) Google Scholar). Small ubiquitin-like modifier (SUMO) is one of the best characterized Ubls from among approximately one dozen Ubl family members identified to date (2Kerscher O. Felberbaum R. Hochstrasser M. Annu. Rev. Cell Dev. Biol. 2006; 22: 159-180Crossref PubMed Scopus (1223) Google Scholar, 3Geiss-Friedlander R. Melchior F. Nat. Rev. Mol. Cell Biol. 2007; 8: 947-956Crossref PubMed Scopus (1359) Google Scholar). The SUMO path-way contributes to the regulation of many cellular processes that include replication, nuclear transport, transcription, recombination, chromosome segregation, and cytokinesis (4Johnson E.S. Annu. Rev. Biochem. 2004; 73: 355-382Crossref PubMed Scopus (1385) Google Scholar). The human SUMO protein family consists of three isoforms, SUMO1, SUMO2, and SUMO3 (see under “Experimental Procedures” for definition of SUMO nomenclature). Mature SUMO1 shares only 43% identity to SUMO2 or SUMO3, whereas SUMO2 and SUMO3 share greater than 95% identity at the primary amino acid level (and are thus referred to as SUMO2/3 in some instances). SUMO4 was recently identified as a fourth SUMO family member (5Bohren K.M. Nadkarni V. Song J.H. Gabbay K.H. Owerbach D.A. J. Biol. Chem. 2004; 279: 27233-27238Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar), although it remains unclear whether SUMO4 participates in formation of SUMO conjugates in vivo (6Owerbach D. McKay E.M. Yeh E.T. Gabbay K.H. Bohren K.M. Biochem. Biophys. Res. Commun. 2005; 337: 517-520Crossref PubMed Scopus (181) Google Scholar). A cascade of SUMO-specific E1-E2-E3 enzymes is required to promote SUMO conjugation, whereas SUMO-specific proteases are required to catalyze SUMO deconjugation (1Hershko A. Ciechanover A. Annu. Rev. Biochem. 1998; 67: 425-479Crossref PubMed Scopus (6907) Google Scholar, 4Johnson E.S. Annu. Rev. Biochem. 2004; 73: 355-382Crossref PubMed Scopus (1385) Google Scholar, 7Li S.-J. Hochstrasser M. Nature. 1999; 398: 246-251Crossref PubMed Scopus (605) Google Scholar). SUMO isoforms contribute to nonredundant functions in the cell as evidenced by the observation that some proteins appear modified exclusively with SUMO1 or SUMO2/3, whereas other substrates can be modified with either SUMO1 or SUMO2/3 (8Saitoh H. Hinchey J. J. Biol. Chem. 2000; 275: 6252-6258Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar, 9Vertegaal A.C. Andersen J.S. Ogg S.C. Hay R.T. Mann M. Lamond A.I. Mol. Cell. Proteomics. 2006; 5: 2298-2310Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar). In addition, SUMO1 and SUMO2/3 exhibit different dynamics in vivo in response to stimuli such as oxidative stress or heat shock (10Ayaydin F. Dasso M. Mol. Biol. Cell. 2004; 15: 5208-5218Crossref PubMed Scopus (159) Google Scholar, 11Bossis G. Melchior F. Mol. 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J. Biol. Chem. 2003; 278: 44113-44120Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). Other evidence suggests that SUMO2/3 chains might contribute to Aβ production (15Li Y. Wang H. Wang S. Quon D. Liu Y.W. Cordell B. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 259-264Crossref PubMed Scopus (128) Google Scholar) and promyelocytic leukemia protein stability (16Fu C. Ahmed K. Ding H. Ding X. Lan J. Yang Z. Miao Y. Zhu Y. Shi Y. Zhu J. Huang H. Yao X. Oncogene. 2005; 24: 5401-5413Crossref PubMed Scopus (90) Google Scholar). More recently, poly-SUMO chains were proposed to recruit a ubiquitin ligase that targets the substrate or chains for ubiquitin-mediated proteolysis (i.e. SUMO-modified PML (17Tatham M.H. Geoffroy M.C. Shen L. Plechanovova A. Hattersley N. Jaffray E.G. Palvimo J.J. Hay R.T. Nat. Cell Biol. 2008; 10: 538-546Crossref PubMed Scopus (660) Google Scholar, 18Lallemand-Breitenbach V. Jeanne M. Benhenda S. Nasr R. Lei M. Peres L. Zhou J. Zhu J. Raught B. de Thé H. Nat. Cell Biol. 2008; 10: 547-555Crossref PubMed Scopus (564) Google Scholar)). SUMO proteases contribute to two distinct activities in the cell, processing SUMO precursors to generate mature SUMO and deconjugation of SUMO-conjugated substrates to release mature SUMO and the respective substrate. Cleavage occurs after the conserved SUMO Gly-Gly motif either at the scissile peptide bond during processing or at the scissile isopeptide bond during deconjugation (7Li S.-J. Hochstrasser M. Nature. 1999; 398: 246-251Crossref PubMed Scopus (605) Google Scholar). SUMO proteases are called SENP in human and ULP in yeast. SENP/ULP proteins include conserved catalytic domains that are both necessary and sufficient to promote SUMO deconjugation and maturation activity in vitro. The human SENP protease family includes six family members termed SENP1, SENP2, SENP3, SENP5, SENP6, and SENP7 (19Mukhopadhyay D. Dasso M. Trends Biochem. Sci. 2007; 32: 286-295Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar), each of which share between 20 and 60% sequence identity to each other within their respective catalytic domains. SENP/ULP catalytic domains are not always specific for SUMO. Whereas human DEN1 shares some similarities with other SUMO protease catalytic domains (20Gan-Erdene T. Nagamalleswari K. Yin L. Wu K. Pan Z.Q. Wilkinson K.D. J. Biol. Chem. 2003; 278: 28892-28900Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 21Wu K. Yamoah K. Dolios G. Gan-Erdene T. Tan P. Chen A. Lee C.G. Wei N. Wilkinson K.D. Wang R. Pan Z.Q. J. Biol. Chem. 2003; 278: 28882-28891Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, D. Wu K. Pan Z.Q. Wilkinson K.D. J. Mol. Biol. 2005; PubMed Scopus Google Scholar, Liu H. C. D. Naismith J.H. Hay R.T. 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SENP1 a for any SUMO whereas SENP2 a for SUMO2/3 SENP6 and SENP7 constitute the most divergent subclass within the SENP/ULP one that includes yeast (19Mukhopadhyay D. Dasso M. Trends Biochem. Sci. 2007; 32: 286-295Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar). In to lower sequence within the catalytic SENP6 and SENP7 include conserved sequence in distinct within their catalytic domains. subclass of SENP/ULP proteases, assays to the activities of SENP6 and SENP7 in comparison with SENP2. SENP6 and SENP7 exhibit for SUMO2/3, or chains are used as The structure for the SENP7 catalytic domain was at and mutational analysis unique elements conserved within SENP6 and SENP7 that contribute to substrate and catalytic Protein catalytic domains of human and were by human and and to a to a N-terminal were used to were grown by at to and was to a of were for at and by and the was Cell were in 20 20 and 20 and were by Cell was by Protein was from by and with and and and with at a SENP6 and SENP7 were by the protein of were to to and with a from to of a and in the protein of were to and in to at were the SENP7 the was used to SENP7 by amino by two glycine residues for the between residues and and by amino to were by SENP7 and isoforms were by and and to in a and SENP2, SUMO and conjugates were as previously D. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Nat. Mol. Biol. 2006; PubMed Scopus Google Scholar). di-SUMO3, and chains were from Biochem. was for SUMO isoforms with with and pre-SUMO3 with Biochemical and assays were in C-terminal activity was by pre-SUMO1, pre-SUMO2, and pre-SUMO3 proteins with SENP6 or SENP7 and SENP7 isoforms at three different enzyme and at in a and were after with and by were by with or conditions were used to deconjugation activities for SENP2, SENP6, and SENP7 and isoforms at and di-SUMO2, di-SUMO3, and at of the of poly-SUMO or at a to that used for substrates were after with and by were by with or were by under a with for deconjugation were for SENP7 and isoforms the substrate in a and were at with and by were by with or and Data of the SENP7 catalytic domain were at by The and after from of protein in and were in and in to were from at Data were and Z. 276: PubMed Scopus Google Scholar), and D. 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SENP6 and SENP7 at and was previously to and chains in a that for PML D. F. N. Tan T. A. Y. Wilkinson K.D. Dasso M. J. Cell Biol. 2006; PubMed Scopus Google Scholar). We next SENP6 and SENP7 catalytic domains for their to promote deconjugation of or poly-SUMO2/3 chains distinct SUMO substrates as and di-SUMO3, which two SUMO by an isopeptide bond between the C-terminal glycine in one SUMO and in the other of and and which are composed of chains between two and greater than SUMO via the isopeptide assays different enzyme for SENP2, SENP6, and SENP7 and and for respective substrates (see “Experimental In each cleavage were for SENP2, SENP6, and although SENP6 to catalyze poly-SUMO2/3 deconjugation at rates in comparison with either SENP2 or can be best in which the of the of the respective In SENP6 and SENP7 were at cleavage of or in comparison with reactions SENP2. The in each that SENP2, SENP6, or SENP7 catalytic domains a than to SUMO chains. of were for the SENP7 catalytic domain that amino acid residues structures of SENP1 and SENP2, the SENP7 structure was by in the of two or The structure one in the and a that was to with an and of and A and and “Experimental The SENP7 structure to the SENP/ULP protease family as as to other members of the protease family the structure of the SENP7 catalytic domain also unique to of SENP/ULP family members include the the of an N-terminal that is present in structures of SENP1, SENP2, and that termed and and structure elements unique or in SENP7 in comparison with SENP1 or SENP2. with SENP7 not to SENP1 of sequence or SENP2 of sequence In contrast, SENP1 and SENP2 exhibit and can be with an of residues with a sequence identity of 60% whether for SENP7 for SUMO2/3, or for SENP7 in complex with SUMO structures of SENP1 and SENP2 that were previously in complex with SUMO or SUMO-conjugated and with SENP1, SENP2, and a protease that for SUMO via an protease that SUMO at from the cleavage D. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L. 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The is and in by a on the SENP7 and contribute to the of and to the that unique to SENP7 is conserved in SENP7 and SENP6 but to in SENP1 and SENP2. which includes residues and by and three glycine residues and in SENP1 or SENP2 or other SENP/ULP family members and In to and which the and are on the of the protease catalytic domain and includes a of amino acid residues between and In includes and although amino of are in structure In SENP6, is and includes amino acid on amino acid that and be present in SENP6, although the elements of the are not is conserved in SENP6 and SENP7 and in SENP7 Whereas and are from the to contribute to in A or as in structures for SENP1 or SENP2 in complex with and might contribute to with a substrate in SENP6 or SENP7 were to a poly-SUMO and Biochemical of and were for the SENP7 catalytic domain to whether the for SUMO processing or isoforms those that or (see “Experimental We not to it was and chains that to the in SENP7 A and In to were for and was for it is conserved as in most SENP/ULP family a residue previously proposed as a for with the SUMO C-terminal and Gly-Gly motif D. Nat. Mol. Biol. 2006; PubMed Scopus Google Scholar). and are in the with SUMO, and are conserved as and in SENP1 and SENP2 and SENP7 to SENP7 during as isoforms from as at with their although not be from or lower (see each protein as and each some catalytic respective not appear to present to protein SENP7 isoforms in and were with SENP7 in reactions for processing each of the three SUMO precursors three different protease and in the of pre-SUMO1, pre-SUMO2, and only SENP2 was for of two glycine residues after the Gly-Gly motif maturation rates for SENP7 with whereas processing rates was used as the substrate of in processing rates in comparison with SENP7 or SENP7 in either or SENP7 and respective isoforms were next for their to and poly-SUMO2/3 substrates assays and different enzyme or with or the of poly-SUMO2/3 was to or poly-SUMO2/3 in comparison with either SENP7 or SENP7 that of either or are with the of in which suggests it the for SUMO substrates in A The of amino acid residues in was by and to amino acid chains that are conserved in SENP1 and SENP2. and assays for and poly-SUMO2/3 deconjugation were or In comparison with deconjugation rates were for whereas not deconjugation rates in comparison with SENP7 is that for present as a The in deconjugation rates for was greater than that for is to it with SUMO2/3 in A but than with SUMO as in with SENP1 and SENP2, analysis suggests that might be in a to to the of the in SUMO2 the of SENP6 and other SENP/ULP family members include a conserved the In SENP6 and is conserved as that the residue an in both peptide and isopeptide substrates the SENP/ULP D. Nat. Mol. Biol. 2006; PubMed Scopus Google Scholar), SENP7 to and the of on deconjugation and deconjugation reactions or poly-SUMO2/3 rates to or greater than SENP7 although in a activity deconjugation rates were (see were SUMO processing activities with SENP7 The of were next by analysis for poly-SUMO2/3 deconjugation SENP7 and the respective isoforms to the rates for deconjugation at of enzyme and substrate “Experimental during assays but in for and a for was at in reactions SENP7 or respective SENP7 isoforms were in comparison with those used for and other SENP7 isoforms with or or in deconjugation In of the within not for in activity were for other SENP7 isoforms, and although most were it is that rates in assays under the conditions most was the observation that SENP7 catalyzed deconjugation at rates than SENP2. This is in to for deconjugation reactions SUMO1 or processing reactions with pre-SUMO1, pre-SUMO2, or pre-SUMO3 the six human SENP/ULP proteases to cleavage and processing of SUMO, SENP6 and SENP7 are the most divergent with to primary sequence and We that SENP6 and SENP7 catalytic domains a for SUMO deconjugation and deconjugation of substrates SUMO2/3 was substrates SENP6 and SENP7 exhibit rates for or poly-SUMO2/3 in comparison with deconjugation of is also that SENP6 was in activities with those catalyzed by SENP7 in for catalytic activities for SENP2, SENP6, and SENP7 and mutational on SENP7 in a analysis that SENP7 is a member of the SENP/ULP protease although to other characterized family members such as SENP1, SENP2, and at the and primary sequence include sequence conserved in SENP6 and SENP7 that in the SENP7 and are on the protease in to with SUMO in A and whereas of on SENP7 activities in the present of in lower activities for of the substrates sequence suggests that is conserved in SENP6 and SENP7 but in other SENP/ULP family to is a residue conserved in SENP6 and residue was to in SENP1 and SENP7 activity was in comparison with is that residues at in structures of SENP1, SENP2, and in to chains conserved in human SUMO1, SUMO2/3, and yeast SMT3 D. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L. 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Lima et al. (Thu,) studied this question.