ID MSH6_YEAST Reviewed; 1242 AA. AC Q03834; D6VS82; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 199. DE RecName: Full=DNA mismatch repair protein MSH6; DE AltName: Full=MutS protein homolog 6; DE AltName: Full=Postmeiotic segregation protein 3; GN Name=MSH6; Synonyms=PMS3; OrderedLocusNames=YDR097C; GN ORFNames=YD8557.04C; OS Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast). OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes; OC Saccharomycetales; Saccharomycetaceae; Saccharomyces. OX NCBI_TaxID=559292; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=ATCC 204508 / S288c; RX PubMed=9169867; RA Jacq C., Alt-Moerbe J., Andre B., Arnold W., Bahr A., Ballesta J.P.G., RA Bargues M., Baron L., Becker A., Biteau N., Bloecker H., Blugeon C., RA Boskovic J., Brandt P., Brueckner M., Buitrago M.J., Coster F., RA Delaveau T., del Rey F., Dujon B., Eide L.G., Garcia-Cantalejo J.M., RA Goffeau A., Gomez-Peris A., Granotier C., Hanemann V., Hankeln T., RA Hoheisel J.D., Jaeger W., Jimenez A., Jonniaux J.-L., Kraemer C., RA Kuester H., Laamanen P., Legros Y., Louis E.J., Moeller-Rieker S., RA Monnet A., Moro M., Mueller-Auer S., Nussbaumer B., Paricio N., Paulin L., RA Perea J., Perez-Alonso M., Perez-Ortin J.E., Pohl T.M., Prydz H., RA Purnelle B., Rasmussen S.W., Remacha M.A., Revuelta J.L., Rieger M., RA Salom D., Saluz H.P., Saiz J.E., Saren A.-M., Schaefer M., Scharfe M., RA Schmidt E.R., Schneider C., Scholler P., Schwarz S., Soler-Mira A., RA Urrestarazu L.A., Verhasselt P., Vissers S., Voet M., Volckaert G., RA Wagner G., Wambutt R., Wedler E., Wedler H., Woelfl S., Harris D.E., RA Bowman S., Brown D., Churcher C.M., Connor R., Dedman K., Gentles S., RA Hamlin N., Hunt S., Jones L., McDonald S., Murphy L.D., Niblett D., RA Odell C., Oliver K., Rajandream M.A., Richards C., Shore L., Walsh S.V., RA Barrell B.G., Dietrich F.S., Mulligan J.T., Allen E., Araujo R., Aviles E., RA Berno A., Carpenter J., Chen E., Cherry J.M., Chung E., Duncan M., RA Hunicke-Smith S., Hyman R.W., Komp C., Lashkari D., Lew H., Lin D., RA Mosedale D., Nakahara K., Namath A., Oefner P., Oh C., Petel F.X., RA Roberts D., Schramm S., Schroeder M., Shogren T., Shroff N., Winant A., RA Yelton M.A., Botstein D., Davis R.W., Johnston M., Andrews S., Brinkman R., RA Cooper J., Ding H., Du Z., Favello A., Fulton L., Gattung S., Greco T., RA Hallsworth K., Hawkins J., Hillier L.W., Jier M., Johnson D., Johnston L., RA Kirsten J., Kucaba T., Langston Y., Latreille P., Le T., Mardis E., RA Menezes S., Miller N., Nhan M., Pauley A., Peluso D., Rifkin L., Riles L., RA Taich A., Trevaskis E., Vignati D., Wilcox L., Wohldman P., Vaudin M., RA Wilson R., Waterston R., Albermann K., Hani J., Heumann K., Kleine K., RA Mewes H.-W., Zollner A., Zaccaria P.; RT "The nucleotide sequence of Saccharomyces cerevisiae chromosome IV."; RL Nature 387:75-78(1997). RN [2] RP GENOME REANNOTATION. RC STRAIN=ATCC 204508 / S288c; RX PubMed=24374639; DOI=10.1534/g3.113.008995; RA Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R., RA Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S., RA Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.; RT "The reference genome sequence of Saccharomyces cerevisiae: Then and now."; RL G3 (Bethesda) 4:389-398(2014). RN [3] RP CHARACTERIZATION. RX PubMed=8723353; DOI=10.1016/s0960-9822(02)00516-x; RA Iaccarino I., Palombo F., Drummond J.T., Totty N.F., Hsuan J.J., RA Modrich P., Jiricny J.; RT "MSH6, a Saccharomyces cerevisiae protein that binds to mismatches as a RT heterodimer with MSH2."; RL Curr. Biol. 6:484-486(1996). RN [4] RP FUNCTION, INTERACTION WITH MSH2, AND MUTAGENESIS OF GLY-421. RX PubMed=8600025; DOI=10.1101/gad.10.4.407; RA Marsischky G.T., Filosi N., Kane M.F., Kolodner R.D.; RT "Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent RT mismatch repair."; RL Genes Dev. 10:407-420(1996). RN [5] RP CHARACTERIZATION, AND INTERACTION WITH MSH2. RX PubMed=8816473; DOI=10.1128/mcb.16.10.5604; RA Alani E.; RT "The Saccharomyces cerevisiae Msh2 and Msh6 proteins form a complex that RT specifically binds to duplex oligonucleotides containing mismatched DNA RT base pairs."; RL Mol. Cell. Biol. 16:5604-5615(1996). RN [6] RP FUNCTION IN MMR. RX PubMed=9111357; DOI=10.1128/mcb.17.5.2851; RA Sia E.A., Kokoska R.J., Dominska M., Greenwell P., Petes T.D.; RT "Microsatellite instability in yeast: dependence on repeat unit size and RT DNA mismatch repair genes."; RL Mol. Cell. Biol. 17:2851-2858(1997). RN [7] RP FUNCTION, DNA-BINDING, AND COMPLEX FORMATION WITH MLH1-PMS1. RX PubMed=9545323; DOI=10.1074/jbc.273.16.9837; RA Habraken Y., Sung P., Prakash L., Prakash S.; RT "ATP-dependent assembly of a ternary complex consisting of a DNA mismatch RT and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes."; RL J. Biol. Chem. 273:9837-9841(1998). RN [8] RP MUTAGENESIS OF GLY-987. RX PubMed=9819445; DOI=10.1128/mcb.18.12.7590; RA Studamire B., Quach T., Alani E.; RT "Saccharomyces cerevisiae Msh2p and Msh6p ATPase activities are both RT required during mismatch repair."; RL Mol. Cell. Biol. 18:7590-7601(1998). RN [9] RP FUNCTION. RX PubMed=9770499; DOI=10.1073/pnas.95.21.12404; RA Flores-Rozas H., Kolodner R.D.; RT "The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent RT suppression of frameshift mutations."; RL Proc. Natl. Acad. Sci. U.S.A. 95:12404-12409(1998). RN [10] RP MUTAGENESIS OF LEU-301 AND GLY-477. RX PubMed=10537275; RA Kolodner R.D., Tytell J.D., Schmeits J.L., Kane M.F., Das Gupta R., RA Weger J., Wahlberg S., Fox E.A., Peel D., Ziogas A., Garber J.E., RA Syngal S., Anton-Culver H., Li F.P.; RT "Germ-line msh6 mutations in colorectal cancer families."; RL Cancer Res. 59:5068-5074(1999). RN [11] RP DNA-BINDING SPECIFICITY. RX PubMed=10066781; DOI=10.1074/jbc.274.11.7200; RA Marsischky G.T., Lee S., Griffith J., Kolodner R.D.; RT "Saccharomyces cerevisiae MSH2/6 complex interacts with Holliday junctions RT and facilitates their cleavage by phage resolution enzymes."; RL J. Biol. Chem. 274:7200-7206(1999). RN [12] RP MUTAGENESIS OF PHE-337. RX PubMed=10347163; DOI=10.1074/jbc.274.23.16115; RA Bowers J., Sokolsky T., Quach T., Alani E.; RT "A mutation in the MSH6 subunit of the Saccharomyces cerevisiae MSH2-MSH6 RT complex disrupts mismatch recognition."; RL J. Biol. Chem. 274:16115-16125(1999). RN [13] RP DNA-BINDING SPECIFICITY. RX PubMed=10480869; DOI=10.1074/jbc.274.38.26668; RA Marsischky G.T., Kolodner R.D.; RT "Biochemical characterization of the interaction between the Saccharomyces RT cerevisiae MSH2-MSH6 complex and mispaired bases in DNA."; RL J. Biol. Chem. 274:26668-26682(1999). RN [14] RP FUNCTION. RX PubMed=10518225; DOI=10.1016/s1097-2765(00)80346-9; RA Ni T.T., Marsischky G.T., Kolodner R.D.; RT "MSH2 and MSH6 are required for removal of adenine misincorporated opposite RT 8-oxo-guanine in S. cerevisiae."; RL Mol. Cell 4:439-444(1999). RN [15] RP INTERACTION WITH POL30, AND MUTAGENESIS OF 26-LYS-GLN-27 AND 33-PHE-PHE-34. RX PubMed=11005803; DOI=10.1074/jbc.c000513200; RA Clark A.B., Valle F., Drotschmann K., Gary R.K., Kunkel T.A.; RT "Functional interaction of proliferating cell nuclear antigen with MSH2- RT MSH6 and MSH2-MSH3 complexes."; RL J. Biol. Chem. 275:36498-36501(2000). RN [16] RP FUNCTION, AND MUTAGENESIS OF PHE-337. RX PubMed=10970737; DOI=10.1006/jmbi.2000.4081; RA Bowers J., Tran P.T., Liskay R.M., Alani E.; RT "Analysis of yeast MSH2-MSH6 suggests that the initiation of mismatch RT repair can be separated into discrete steps."; RL J. Mol. Biol. 302:327-338(2000). RN [17] RP MUTAGENESIS. RX PubMed=10615127; DOI=10.1038/71684; RA Das Gupta R., Kolodner R.D.; RT "Novel dominant mutations in Saccharomyces cerevisiae MSH6."; RL Nat. Genet. 24:53-56(2000). RN [18] RP INTERACTION WITH POL30, AND MUTAGENESIS OF 33-PHE-PHE-34. RX PubMed=11062484; DOI=10.1038/81708; RA Flores-Rozas H., Clark D., Kolodner R.D.; RT "Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an RT active mispair recognition complex."; RL Nat. Genet. 26:375-378(2000). RN [19] RP DNA-BINDING, AND MUTAGENESIS OF PRO-313; PHE-337; GLU-339; GLY-368; RP PRO-370; GLN-393; ARG-412; LYS-848 AND ARG-852. RX PubMed=11641390; DOI=10.1074/jbc.c100450200; RA Drotschmann K., Yang W., Brownewell F.E., Kool E.T., Kunkel T.A.; RT "Asymmetric recognition of DNA local distortion. Structure-based functional RT studies of eukaryotic Msh2-Msh6."; RL J. Biol. Chem. 276:46225-46229(2001). RN [20] RP FUNCTION, AND COMPLEX FORMATION WITH MLH1-PMS1. RX PubMed=11237611; DOI=10.1006/jmbi.2001.4467; RA Bowers J., Tran P.T., Joshi A., Liskay R.M., Alani E.; RT "MSH-MLH complexes formed at a DNA mismatch are disrupted by the PCNA RT sliding clamp."; RL J. Mol. Biol. 306:957-968(2001). RN [21] RP FUNCTION, AND MUTAGENESIS OF GLU-1062. RX PubMed=12509278; DOI=10.1016/s1568-7864(02)00081-2; RA Drotschmann K., Yang W., Kunkel T.A.; RT "Evidence for sequential action of two ATPase active sites in yeast Msh2- RT Msh6."; RL DNA Repair 1:743-753(2002). RN [22] RP MUTAGENESIS OF SER-1036; GLY-1067; HIS-1096 AND GLY-1142. RX PubMed=11986324; DOI=10.1074/jbc.m202282200; RA Hess M.T., Das Gupta R., Kolodner R.D.; RT "Dominant Saccharomyces cerevisiae msh6 mutations cause increased mispair RT binding and decreased dissociation from mispairs by Msh2-Msh6 in the RT presence of ATP."; RL J. Biol. Chem. 277:25545-25553(2002). RN [23] RP FUNCTION. RX PubMed=12820877; DOI=10.1021/bi034602h; RA Antony E., Hingorani M.M.; RT "Mismatch recognition-coupled stabilization of Msh2-Msh6 in an ATP-bound RT state at the initiation of DNA repair."; RL Biochemistry 42:7682-7693(2003). RN [24] RP INTERACTION WITH POL30. RX PubMed=12435741; DOI=10.1074/jbc.c200627200; RA Lau P.J., Kolodner R.D.; RT "Transfer of the MSH2.MSH6 complex from proliferating cell nuclear antigen RT to mispaired bases in DNA."; RL J. Biol. Chem. 278:14-17(2003). RN [25] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RX PubMed=14562095; DOI=10.1038/nature02026; RA Huh W.-K., Falvo J.V., Gerke L.C., Carroll A.S., Howson R.W., RA Weissman J.S., O'Shea E.K.; RT "Global analysis of protein localization in budding yeast."; RL Nature 425:686-691(2003). RN [26] RP LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS]. RX PubMed=14562106; DOI=10.1038/nature02046; RA Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N., RA O'Shea E.K., Weissman J.S.; RT "Global analysis of protein expression in yeast."; RL Nature 425:737-741(2003). RN [27] RP ACTIVITY REGULATION, AND MUTAGENESIS OF GLU-1062. RX PubMed=15513922; DOI=10.1074/jbc.c400495200; RA Clark A.B., Kunkel T.A.; RT "Cadmium inhibits the functions of eukaryotic MutS complexes."; RL J. Biol. Chem. 279:53903-53906(2004). RN [28] RP FUNCTION, AND COMPLEX FORMATION WITH MLH1-PMS1. RX PubMed=15811858; DOI=10.1074/jbc.m407545200; RA Mendillo M.L., Mazur D.J., Kolodner R.D.; RT "Analysis of the interaction between the Saccharomyces cerevisiae MSH2-MSH6 RT and MLH1-PMS1 complexes with DNA using a reversible DNA end-blocking RT system."; RL J. Biol. Chem. 280:22245-22257(2005). RN [29] RP FUNCTION. RX PubMed=16337600; DOI=10.1016/j.molcel.2005.10.014; RA Jiang J., Bai L., Surtees J.A., Gemici Z., Wang M.D., Alani E.; RT "Detection of high-affinity and sliding clamp modes for MSH2-MSH6 by RT single-molecule unzipping force analysis."; RL Mol. Cell 20:771-781(2005). RN [30] RP ACTIVITY REGULATION. RX PubMed=15746000; DOI=10.1093/nar/gki291; RA Banerjee S., Flores-Rozas H.; RT "Cadmium inhibits mismatch repair by blocking the ATPase activity of the RT MSH2-MSH6 complex."; RL Nucleic Acids Res. 33:1410-1419(2005). RN [31] RP FUNCTION, AND MUTAGENESIS OF LYS-988 AND GLU-1062. RX PubMed=16214425; DOI=10.1016/j.dnarep.2005.08.016; RA Antony E., Khubchandani S., Chen S., Hingorani M.M.; RT "Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA RT mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch RT repair protein."; RL DNA Repair 5:153-162(2006). RN [32] RP FUNCTION. RX PubMed=16702432; DOI=10.1534/genetics.106.055616; RA Stone J.E., Petes T.D.; RT "Analysis of the proteins involved in the in vivo repair of base-base RT mismatches and four-base loops formed during meiotic recombination in the RT yeast Saccharomyces cerevisiae."; RL Genetics 173:1223-1239(2006). RN [33] RP FUNCTION, AND MUTAGENESIS OF LYS-988. RX PubMed=16600868; DOI=10.1016/j.molcel.2006.02.010; RA Mazur D.J., Mendillo M.L., Kolodner R.D.; RT "Inhibition of Msh6 ATPase activity by mispaired DNA induces a Msh2(ATP)- RT Msh6(ATP) state capable of hydrolysis-independent movement along DNA."; RL Mol. Cell 22:39-49(2006). RN [34] RP FUNCTION, AND MUTAGENESIS OF SER-1036; GLY-1067 AND GLY-1142. RX PubMed=16407100; DOI=10.1073/pnas.0510078103; RA Hess M.T., Mendillo M.L., Mazur D.J., Kolodner R.D.; RT "Biochemical basis for dominant mutations in the Saccharomyces cerevisiae RT MSH6 gene."; RL Proc. Natl. Acad. Sci. U.S.A. 103:558-563(2006). RN [35] RP FUNCTION, AND MUTAGENESIS OF GLU-339. RX PubMed=17141577; DOI=10.1016/j.dnarep.2006.10.023; RA Holmes S.F., Scarpinato K.D., McCulloch S.D., Schaaper R.M., Kunkel T.A.; RT "Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of RT yeast Msh6."; RL DNA Repair 6:293-303(2007). RN [36] RP FUNCTION. RX PubMed=17157869; DOI=10.1016/j.jmb.2006.10.099; RA Lee S.D., Surtees J.A., Alani E.; RT "Saccharomyces cerevisiae MSH2-MSH3 and MSH2-MSH6 complexes display RT distinct requirements for DNA binding domain I in mismatch recognition."; RL J. Mol. Biol. 366:53-66(2007). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-145 AND SER-150, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC STRAIN=ADR376; RX PubMed=17330950; DOI=10.1021/pr060559j; RA Li X., Gerber S.A., Rudner A.D., Beausoleil S.A., Haas W., Villen J., RA Elias J.E., Gygi S.P.; RT "Large-scale phosphorylation analysis of alpha-factor-arrested RT Saccharomyces cerevisiae."; RL J. Proteome Res. 6:1190-1197(2007). RN [38] RP FUNCTION, AND DNA-BINDING DOMAIN. RX PubMed=17567610; DOI=10.1093/nar/gkm409; RA Clark A.B., Deterding L., Tomer K.B., Kunkel T.A.; RT "Multiple functions for the N-terminal region of Msh6."; RL Nucleic Acids Res. 35:4114-4123(2007). RN [39] RP FUNCTION. RX PubMed=17573527; DOI=10.1073/pnas.0704148104; RA Shell S.S., Putnam C.D., Kolodner R.D.; RT "Chimeric Saccharomyces cerevisiae Msh6 protein with an Msh3 mispair- RT binding domain combines properties of both proteins."; RL Proc. Natl. Acad. Sci. U.S.A. 104:10956-10961(2007). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=17287358; DOI=10.1073/pnas.0607084104; RA Chi A., Huttenhower C., Geer L.Y., Coon J.J., Syka J.E.P., Bai D.L., RA Shabanowitz J., Burke D.J., Troyanskaya O.G., Hunt D.F.; RT "Analysis of phosphorylation sites on proteins from Saccharomyces RT cerevisiae by electron transfer dissociation (ETD) mass spectrometry."; RL Proc. Natl. Acad. Sci. U.S.A. 104:2193-2198(2007). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-102; SER-145; SER-150 AND RP THR-451, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=18407956; DOI=10.1074/mcp.m700468-mcp200; RA Albuquerque C.P., Smolka M.B., Payne S.H., Bafna V., Eng J., Zhou H.; RT "A multidimensional chromatography technology for in-depth phosphoproteome RT analysis."; RL Mol. Cell. Proteomics 7:1389-1396(2008). RN [42] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-145; SER-150 AND SER-201, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19779198; DOI=10.1126/science.1172867; RA Holt L.J., Tuch B.B., Villen J., Johnson A.D., Gygi S.P., Morgan D.O.; RT "Global analysis of Cdk1 substrate phosphorylation sites provides insights RT into evolution."; RL Science 325:1682-1686(2009). CC -!- FUNCTION: Component of the post-replicative DNA mismatch repair system CC (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA CC mismatches thereby initiating DNA repair. MSH6 provides substrate- CC binding and substrate specificity to the complex. When bound, MutS CC alpha bends the DNA helix and shields approximately 20 base pairs. Acts CC mainly to repair base-base and single insertion-deletion mismatches CC that occur during replication, but can also repair longer insertion- CC deletion loops (IDLs), although with decreasing efficiency as the size CC of the extrahelical loop increases. After mismatch binding, forms a CC ternary complex with the MutL alpha heterodimer, which is thought to be CC responsible for directing the downstream MMR events, including strand CC discrimination, excision, and resynthesis. ATP binding and hydrolysis CC by the MutS alpha complex is crucial for MMR. Both subunits bind ATP, CC but with differing affinities, and their ATPase kinetics are also very CC different. MSH6 binds and hydrolyzes ATP rapidly, whereas MSH2 CC catalyzes ATP at a substantially slower rate. Binding to a mismatched CC base pair suppresses MSH6-catalyzed ATP hydrolysis, but not the CC activity of MSH2. ATP binding to both subunits is necessary to trigger CC a change in MutS alpha interaction with mismatched DNA, converting MutS CC alpha into a sliding clamp capable of hydrolysis-independent movement CC along DNA, and also facilitates formation of ternary complexes CC containing MutS and MutL proteins and the mismatch. May also be CC involved in resolution of recombination intermediates. CC {ECO:0000269|PubMed:10518225, ECO:0000269|PubMed:10970737, CC ECO:0000269|PubMed:11237611, ECO:0000269|PubMed:12509278, CC ECO:0000269|PubMed:12820877, ECO:0000269|PubMed:15811858, CC ECO:0000269|PubMed:16214425, ECO:0000269|PubMed:16337600, CC ECO:0000269|PubMed:16407100, ECO:0000269|PubMed:16600868, CC ECO:0000269|PubMed:16702432, ECO:0000269|PubMed:17141577, CC ECO:0000269|PubMed:17157869, ECO:0000269|PubMed:17567610, CC ECO:0000269|PubMed:17573527, ECO:0000269|PubMed:8600025, CC ECO:0000269|PubMed:9111357, ECO:0000269|PubMed:9545323, CC ECO:0000269|PubMed:9770499}. CC -!- ACTIVITY REGULATION: Inhibited by Cd(2+). {ECO:0000269|PubMed:15513922, CC ECO:0000269|PubMed:15746000}. CC -!- SUBUNIT: Heterodimer consisting of MSH2-MSH6 (MutS alpha). Forms a CC ternary complex with MutL alpha (MLH1-PMS1). MutS alpha interacts with CC proliferating cell nuclear antigen (PCNA/POL30). This interaction is CC disrupted upon binding of MutS alpha to mismatch DNA. CC {ECO:0000269|PubMed:11005803, ECO:0000269|PubMed:11062484, CC ECO:0000269|PubMed:12435741, ECO:0000269|PubMed:8600025, CC ECO:0000269|PubMed:8816473}. CC -!- INTERACTION: CC Q03834; P25847: MSH2; NbExp=6; IntAct=EBI-11383, EBI-11352; CC Q03834; P15873: POL30; NbExp=5; IntAct=EBI-11383, EBI-12993; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:14562095}. CC -!- DOMAIN: The PIP box serves as a PCNA(POL30)-recognition and -binding CC motif. CC -!- MISCELLANEOUS: Present with 5330 molecules/cell in log phase SD medium. CC {ECO:0000269|PubMed:14562106}. CC -!- SIMILARITY: Belongs to the DNA mismatch repair MutS family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Z47746; CAA87671.1; -; Genomic_DNA. DR EMBL; BK006938; DAA11942.1; -; Genomic_DNA. DR PIR; S51246; S51246. DR RefSeq; NP_010382.3; NM_001180405.3. DR AlphaFoldDB; Q03834; -. DR SMR; Q03834; -. DR BioGRID; 32152; 131. DR ComplexPortal; CPX-1037; DNA mismatch repair MutSalpha complex. DR DIP; DIP-2423N; -. DR ELM; Q03834; -. DR IntAct; Q03834; 35. DR MINT; Q03834; -. DR STRING; 4932.YDR097C; -. DR iPTMnet; Q03834; -. DR MaxQB; Q03834; -. DR PaxDb; 4932-YDR097C; -. DR PeptideAtlas; Q03834; -. DR EnsemblFungi; YDR097C_mRNA; YDR097C; YDR097C. DR GeneID; 851671; -. DR KEGG; sce:YDR097C; -. DR AGR; SGD:S000002504; -. DR SGD; S000002504; MSH6. DR VEuPathDB; FungiDB:YDR097C; -. DR eggNOG; KOG0217; Eukaryota. DR GeneTree; ENSGT00550000075024; -. DR HOGENOM; CLU_002472_1_0_1; -. DR InParanoid; Q03834; -. DR OMA; TPMMAQY; -. DR OrthoDB; 168255at2759; -. DR BioCyc; YEAST:G3O-29700-MONOMER; -. DR Reactome; R-SCE-5358565; Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha). DR BioGRID-ORCS; 851671; 3 hits in 10 CRISPR screens. DR PRO; PR:Q03834; -. DR Proteomes; UP000002311; Chromosome IV. DR RNAct; Q03834; Protein. DR GO; GO:0005737; C:cytoplasm; HDA:SGD. DR GO; GO:0032301; C:MutSalpha complex; IPI:SGD. DR GO; GO:0005634; C:nucleus; HDA:SGD. DR GO; GO:0005524; F:ATP binding; IDA:SGD. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:SGD. DR GO; GO:0140664; F:ATP-dependent DNA damage sensor activity; IEA:InterPro. DR GO; GO:0000400; F:four-way junction DNA binding; IDA:SGD. DR GO; GO:0030983; F:mismatched DNA binding; IBA:GO_Central. DR GO; GO:0003676; F:nucleic acid binding; EXP:DisProt. DR GO; GO:0036297; P:interstrand cross-link repair; IGI:SGD. DR GO; GO:0000710; P:meiotic mismatch repair; IMP:SGD. DR GO; GO:0006298; P:mismatch repair; IDA:SGD. DR GO; GO:0043111; P:replication fork arrest; IMP:SGD. DR DisProt; DP01623; -. DR Gene3D; 1.10.1420.10; -; 2. DR Gene3D; 3.40.1170.10; DNA repair protein MutS, domain I; 1. DR Gene3D; 3.30.420.110; MutS, connector domain; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR007695; DNA_mismatch_repair_MutS-lik_N. DR InterPro; IPR017261; DNA_mismatch_repair_MutS/MSH. DR InterPro; IPR000432; DNA_mismatch_repair_MutS_C. DR InterPro; IPR007861; DNA_mismatch_repair_MutS_clamp. DR InterPro; IPR007696; DNA_mismatch_repair_MutS_core. DR InterPro; IPR016151; DNA_mismatch_repair_MutS_N. DR InterPro; IPR036187; DNA_mismatch_repair_MutS_sf. DR InterPro; IPR007860; DNA_mmatch_repair_MutS_con_dom. DR InterPro; IPR036678; MutS_con_dom_sf. DR InterPro; IPR045076; MutS_family. DR InterPro; IPR027417; P-loop_NTPase. DR PANTHER; PTHR11361:SF148; DNA MISMATCH REPAIR PROTEIN MSH6; 1. DR PANTHER; PTHR11361; DNA MISMATCH REPAIR PROTEIN MUTS FAMILY MEMBER; 1. DR Pfam; PF01624; MutS_I; 1. DR Pfam; PF05188; MutS_II; 1. DR Pfam; PF05192; MutS_III; 1. DR Pfam; PF05190; MutS_IV; 1. DR Pfam; PF00488; MutS_V; 1. DR PIRSF; PIRSF037677; DNA_mis_repair_Msh6; 1. DR SMART; SM00534; MUTSac; 1. DR SMART; SM00533; MUTSd; 1. DR SUPFAM; SSF55271; DNA repair protein MutS, domain I; 1. DR SUPFAM; SSF53150; DNA repair protein MutS, domain II; 1. DR SUPFAM; SSF48334; DNA repair protein MutS, domain III; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS00486; DNA_MISMATCH_REPAIR_2; 1. PE 1: Evidence at protein level; KW ATP-binding; DNA damage; DNA repair; DNA-binding; Nucleotide-binding; KW Nucleus; Phosphoprotein; Reference proteome. FT CHAIN 1..1242 FT /note="DNA mismatch repair protein MSH6" FT /id="PRO_0000115213" FT DNA_BIND 228..299 FT REGION 1..271 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 305..421 FT /note="Mispair-binding domain" FT MOTIF 27..34 FT /note="PIP box" FT COMPBIAS 9..67 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 88..128 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 129..168 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 169..190 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 213..234 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 245..268 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 982..989 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255" FT MOD_RES 102 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18407956" FT MOD_RES 145 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17330950, FT ECO:0007744|PubMed:18407956, ECO:0007744|PubMed:19779198" FT MOD_RES 150 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17330950, FT ECO:0007744|PubMed:18407956, ECO:0007744|PubMed:19779198" FT MOD_RES 201 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19779198" FT MOD_RES 451 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18407956" FT MUTAGEN 26..27 FT /note="KQ->AA: Partially functional in a mismatch repair FT assay; when associated with 33-AA-34." FT /evidence="ECO:0000269|PubMed:11005803" FT MUTAGEN 33..34 FT /note="FF->AA: Abolishes interaction with PCNA (POL30), but FT only causes a moderate mismatch repair defect. Partially FT functional in a mismatch repair assay; when associated with FT 26-AA-27." FT /evidence="ECO:0000269|PubMed:11005803, FT ECO:0000269|PubMed:11062484" FT MUTAGEN 301 FT /note="L->V: Fully functional in a mismatch repair assay." FT /evidence="ECO:0000269|PubMed:10537275" FT MUTAGEN 313 FT /note="P->A: Fully functional in a mismatch repair assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 337 FT /note="F->A: Shows defects in both homoduplex and mispair FT DNA binding and is only partially functional in a mismatch FT repair assay." FT /evidence="ECO:0000269|PubMed:10347163, FT ECO:0000269|PubMed:10970737, ECO:0000269|PubMed:11641390" FT MUTAGEN 337 FT /note="F->H,I,Y: Partially functional in a mismatch repair FT assay." FT /evidence="ECO:0000269|PubMed:10347163, FT ECO:0000269|PubMed:10970737, ECO:0000269|PubMed:11641390" FT MUTAGEN 337 FT /note="F->K: Completely abolishes mismatch repair." FT /evidence="ECO:0000269|PubMed:10347163, FT ECO:0000269|PubMed:10970737, ECO:0000269|PubMed:11641390" FT MUTAGEN 337 FT /note="F->S: In MSH6-6; partially functional in a mismatch FT repair assay." FT /evidence="ECO:0000269|PubMed:10347163, FT ECO:0000269|PubMed:10970737, ECO:0000269|PubMed:11641390" FT MUTAGEN 339 FT /note="E->A: Defective in repairing 8-oxo-G-A mismatches." FT /evidence="ECO:0000269|PubMed:11641390, FT ECO:0000269|PubMed:17141577" FT MUTAGEN 340..343 FT /note="LYEK->CFAE: In MSH6-340; shows defects in mispair FT DNA binding, but not in homoduplex DNA binding." FT /evidence="ECO:0000269|PubMed:10615127" FT MUTAGEN 368 FT /note="G->A: Moderately reduced activity in a mismatch FT repair assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 370 FT /note="P->A: Partially functional in a mismatch repair FT assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 393 FT /note="Q->A: Moderately reduced activity in a mismatch FT repair assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 393 FT /note="Q->R: In MSH6-5; partially functional in a mismatch FT repair assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 412 FT /note="R->A: Completely abolishes mismatch repair." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 412 FT /note="R->G: In MSH6-7; partially functional in a mismatch FT repair assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 421 FT /note="G->D: In PMS3-1; completely abolishes mismatch FT repair." FT /evidence="ECO:0000269|PubMed:8600025" FT MUTAGEN 477 FT /note="G->R: Partially functional in a mismatch repair FT assay." FT /evidence="ECO:0000269|PubMed:10537275" FT MUTAGEN 848 FT /note="K->A: Fully functional in a mismatch repair assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 852 FT /note="R->A: Moderately reduced activity in a mismatch FT repair assay." FT /evidence="ECO:0000269|PubMed:11641390" FT MUTAGEN 987 FT /note="G->D: Has no defect in mismatch DNA binding, but FT lacks ATP-induced conformational change." FT /evidence="ECO:0000269|PubMed:9819445" FT MUTAGEN 988 FT /note="K->A: Impairs ATP binding; reduces catalytic FT activity 13-fold for ATP hydrolysis." FT /evidence="ECO:0000269|PubMed:16214425, FT ECO:0000269|PubMed:16600868" FT MUTAGEN 1036 FT /note="S->P: In MSH6-4; defective for ATP-induced sliding FT clamp formation and assembly of ternary complexes with MutL FT alpha." FT /evidence="ECO:0000269|PubMed:11986324, FT ECO:0000269|PubMed:16407100" FT MUTAGEN 1062 FT /note="E->A: Reduces catalytic activity 13-fold for ATP FT hydrolysis." FT /evidence="ECO:0000269|PubMed:12509278, FT ECO:0000269|PubMed:15513922, ECO:0000269|PubMed:16214425" FT MUTAGEN 1067 FT /note="G->D: In MSH6-3; defective for ATP-induced sliding FT clamp formation and assembly of ternary complexes with MutL FT alpha." FT /evidence="ECO:0000269|PubMed:11986324, FT ECO:0000269|PubMed:16407100" FT MUTAGEN 1096 FT /note="H->A: In MSH6-9; shows normal mispair binding and FT dissociation, but fails to show complete mispair activation FT of the ATPase." FT /evidence="ECO:0000269|PubMed:11986324" FT MUTAGEN 1142 FT /note="G->D: In MSH6-2; defective for ATP-induced sliding FT clamp formation, but assembles ternary complexes with MutL FT alpha." FT /evidence="ECO:0000269|PubMed:11986324, FT ECO:0000269|PubMed:16407100" SQ SEQUENCE 1242 AA; 140080 MW; 11A6883AADCFA222 CRC64; MAPATPKTSK TAHFENGSTS SQKKMKQSSL LSFFSKQVPS GTPSKKVQKP TPATLENTAT DKITKNPQGG KTGKLFVDVD EDNDLTIAEE TVSTVRSDIM HSQEPQSDTM LNSNTTEPKS TTTDEDLSSS QSRRNHKRRV NYAESDDDDS DTTFTAKRKK GKVVDSESDE DEYLPDKNDG DEDDDIADDK EDIKGELAED SGDDDDLISL AETTSKKKFS YNTSHSSSPF TRNISRDNSK KKSRPNQAPS RSYNPSHSQP SATSKSSKFN KQNEERYQWL VDERDAQRRP KSDPEYDPRT LYIPSSAWNK FTPFEKQYWE IKSKMWDCIV FFKKGKFFEL YEKDALLANA LFDLKIAGGG RANMQLAGIP EMSFEYWAAQ FIQMGYKVAK VDQRESMLAK EMREGSKGIV KRELQCILTS GTLTDGDMLH SDLATFCLAI REEPGNFYNE TQLDSSTIVQ KLNTKIFGAA FIDTATGELQ MLEFEDDSEC TKLDTLMSQV RPMEVVMERN NLSTLANKIV KFNSAPNAIF NEVKAGEEFY DCDKTYAEII SSEYFSTEED WPEVLKSYYD TGKKVGFSAF GGLLYYLKWL KLDKNLISMK NIKEYDFVKS QHSMVLDGIT LQNLEIFSNS FDGSDKGTLF KLFNRAITPM GKRMMKKWLM HPLLRKNDIE SRLDSVDSLL QDITLREQLE ITFSKLPDLE RMLARIHSRT IKVKDFEKVI TAFETIIELQ DSLKNNDLKG DVSKYISSFP EGLVEAVKSW TNAFERQKAI NENIIVPQRG FDIEFDKSMD RIQELEDELM EILMTYRKQF KCSNIQYKDS GKEIYTIEIP ISATKNVPSN WVQMAANKTY KRYYSDEVRA LARSMAEAKE IHKTLEEDLK NRLCQKFDAH YNTIWMPTIQ AISNIDCLLA ITRTSEYLGA PSCRPTIVDE VDSKTNTQLN GFLKFKSLRH PCFNLGATTA KDFIPNDIEL GKEQPRLGLL TGANAAGKST ILRMACIAVI MAQMGCYVPC ESAVLTPIDR IMTRLGANDN IMQGKSTFFV ELAETKKILD MATNRSLLVV DELGRGGSSS DGFAIAESVL HHVATHIQSL GFFATHYGTL ASSFKHHPQV RPLKMSILVD EATRNVTFLY KMLEGQSEGS FGMHVASMCG ISKEIIDNAQ IAADNLEHTS RLVKERDLAA NNLNGEVVSV PGGLQSDFVR IAYGDGLKNT KLGSGEGVLN YDWNIKRNVL KSLFSIIDDL QS //