MSH6_MOUSE
ID MSH6_MOUSE Reviewed; 1358 AA.
AC P54276; O54710; Q6GTK8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=DNA mismatch repair protein Msh6 {ECO:0000303|PubMed:9390556};
DE AltName: Full=G/T mismatch-binding protein {ECO:0000303|PubMed:8812455};
DE Short=GTBP {ECO:0000250|UniProtKB:P52701};
DE Short=GTMBP {ECO:0000303|PubMed:8812455};
DE AltName: Full=MutS protein homolog 6 {ECO:0000250|UniProtKB:P52701};
DE AltName: Full=MutS-alpha 160 kDa subunit;
DE Short=p160 {ECO:0000250|UniProtKB:P52701};
GN Name=Msh6 {ECO:0000312|MGI:MGI:1343961}; Synonyms=Gtmbp;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8812455; DOI=10.1006/geno.1996.0464;
RA Corradi A., Croci L., Stayton C.L., Gulisano M., Boncinelli E.,
RA Consalez G.G.;
RT "cDNA sequence, map, and expression of the murine homolog of GTBP, a DNA
RT mismatch repair gene.";
RL Genomics 36:288-295(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/Ola;
RX PubMed=9390556; DOI=10.1016/s0092-8674(00)80433-x;
RA Edelmann W., Yang K., Umar A., Heyer J., Lau K., Fan K., Liedtke W.,
RA Cohen P., Kane M.K., Lipford J.R., Yu N., Crouse G.F., Pollard J.W.,
RA Kunkel T., Lipkin M., Kolodner R., Kucherlapati R.;
RT "Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.";
RL Cell 91:467-477(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 375-425 AND 1001-1050.
RA Donohue P.J., Feng S.L.Y., Alberts G.F., Guo Y., Peifley K.A., Hsu D.K.W.,
RA Winkles J.A.;
RL Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-261, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-137; SER-252; SER-254;
RP SER-256 AND SER-261, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Kidney, Liver, Lung, Pancreas, Spleen,
RC and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
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. When bound, MutS alpha bends
CC the DNA helix and shields approximately 20 base pairs, and recognizes
CC single base mismatches and dinucleotide insertion-deletion loops (IDL)
CC in the DNA. After mismatch binding, forms a ternary complex with the
CC MutL alpha heterodimer, which is thought to be responsible for
CC directing the downstream MMR events, including strand discrimination,
CC excision, and resynthesis. ATP binding and hydrolysis play a pivotal
CC role in mismatch repair functions. The ATPase activity associated with
CC MutS alpha regulates binding similar to a molecular switch: mismatched
CC DNA provokes ADP-->ATP exchange, resulting in a discernible
CC conformational transition that converts MutS alpha into a sliding clamp
CC capable of hydrolysis-independent diffusion along the DNA backbone.
CC This transition is crucial for mismatch repair. MutS alpha may also
CC play a role in DNA homologous recombination repair. Recruited on
CC chromatin in G1 and early S phase via its PWWP domain that specifically
CC binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early
CC recruitment to chromatin to be replicated allowing a quick
CC identification of mismatch repair to initiate the DNA mismatch repair
CC reaction (By similarity). {ECO:0000250|UniProtKB:P52701}.
CC -!- SUBUNIT: Component of the DNA mismatch repair (MMR) complex composed at
CC least of MSH2, MSH3, MSH6, PMS1 and MLH1. Heterodimer consisting of
CC MSH2-MSH6 (MutS alpha). Forms a ternary complex with MutL alpha (MLH1-
CC PMS1). Interacts with MCM9. Part of the BRCA1-associated genome
CC surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1,
CC ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This
CC association could be a dynamic process changing throughout the cell
CC cycle and within subnuclear domains. {ECO:0000250|UniProtKB:P52701}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P52701}.
CC Chromosome {ECO:0000250|UniProtKB:P52701}. Note=Associates with
CC H3K36me3 via its PWWP domain. {ECO:0000250|UniProtKB:P52701}.
CC -!- DOMAIN: The PWWP domain specifically recognizes and binds trimethylated
CC 'Lys-36' of histone H3 (H3K36me3). {ECO:0000250|UniProtKB:P52701}.
CC -!- PTM: Phosphorylated by PRKCZ, which may prevent MutS alpha degradation
CC by the ubiquitin-proteasome pathway. {ECO:0000250|UniProtKB:P52701}.
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; U42190; AAC53034.1; -; mRNA.
DR EMBL; AF031087; AAB88445.1; -; Genomic_DNA.
DR EMBL; AF031085; AAB88445.1; JOINED; Genomic_DNA.
DR EMBL; AF031086; AAB88445.1; JOINED; Genomic_DNA.
DR EMBL; BC051160; AAH51160.1; -; mRNA.
DR EMBL; BC051634; AAH51634.1; -; mRNA.
DR EMBL; U61388; AAB39930.1; -; mRNA.
DR EMBL; U61389; AAB39931.1; -; mRNA.
DR CCDS; CCDS29021.1; -.
DR RefSeq; NP_034960.1; NM_010830.2.
DR AlphaFoldDB; P54276; -.
DR SMR; P54276; -.
DR BioGRID; 201528; 20.
DR ComplexPortal; CPX-81; DNA mismatch repair MutSalpha complex.
DR CORUM; P54276; -.
DR IntAct; P54276; 5.
DR MINT; P54276; -.
DR STRING; 10090.ENSMUSP00000005503; -.
DR iPTMnet; P54276; -.
DR PhosphoSitePlus; P54276; -.
DR SwissPalm; P54276; -.
DR EPD; P54276; -.
DR jPOST; P54276; -.
DR MaxQB; P54276; -.
DR PaxDb; P54276; -.
DR PeptideAtlas; P54276; -.
DR PRIDE; P54276; -.
DR ProteomicsDB; 290100; -.
DR Antibodypedia; 3963; 753 antibodies from 45 providers.
DR DNASU; 17688; -.
DR Ensembl; ENSMUST00000005503; ENSMUSP00000005503; ENSMUSG00000005370.
DR GeneID; 17688; -.
DR KEGG; mmu:17688; -.
DR UCSC; uc008dvd.2; mouse.
DR CTD; 2956; -.
DR MGI; MGI:1343961; Msh6.
DR VEuPathDB; HostDB:ENSMUSG00000005370; -.
DR eggNOG; KOG0217; Eukaryota.
DR GeneTree; ENSGT00550000075024; -.
DR HOGENOM; CLU_002472_1_3_1; -.
DR InParanoid; P54276; -.
DR OMA; TPMMAQY; -.
DR OrthoDB; 138168at2759; -.
DR PhylomeDB; P54276; -.
DR TreeFam; TF105842; -.
DR Reactome; R-MMU-5358565; Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
DR BioGRID-ORCS; 17688; 1 hit in 114 CRISPR screens.
DR ChiTaRS; Msh6; mouse.
DR PRO; PR:P54276; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; P54276; protein.
DR Bgee; ENSMUSG00000005370; Expressed in animal zygote and 249 other tissues.
DR ExpressionAtlas; P54276; baseline and differential.
DR Genevisible; P54276; MM.
DR GO; GO:0000785; C:chromatin; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0032301; C:MutSalpha complex; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0043531; F:ADP binding; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0008094; F:ATP-dependent activity, acting on DNA; ISO:MGI.
DR GO; GO:0140664; F:ATP-dependent DNA damage sensor activity; IEA:InterPro.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0003684; F:damaged DNA binding; IMP:MGI.
DR GO; GO:0003677; F:DNA binding; IMP:MGI.
DR GO; GO:0003690; F:double-stranded DNA binding; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0000400; F:four-way junction DNA binding; ISO:MGI.
DR GO; GO:0032137; F:guanine/thymine mispair binding; IDA:MGI.
DR GO; GO:0000287; F:magnesium ion binding; ISO:MGI.
DR GO; GO:0035064; F:methylated histone binding; ISS:UniProtKB.
DR GO; GO:0030983; F:mismatched DNA binding; ISS:UniProtKB.
DR GO; GO:0032405; F:MutLalpha complex binding; ISO:MGI.
DR GO; GO:0032357; F:oxidized purine DNA binding; ISO:MGI.
DR GO; GO:0032142; F:single guanine insertion binding; ISO:MGI.
DR GO; GO:0032143; F:single thymine insertion binding; ISO:MGI.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:MGI.
DR GO; GO:0006281; P:DNA repair; ISO:MGI.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IMP:MGI.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:MGI.
DR GO; GO:0045190; P:isotype switching; IMP:MGI.
DR GO; GO:0006298; P:mismatch repair; IMP:MGI.
DR GO; GO:0045910; P:negative regulation of DNA recombination; IMP:MGI.
DR GO; GO:0051096; P:positive regulation of helicase activity; ISO:MGI.
DR GO; GO:0009411; P:response to UV; IMP:MGI.
DR GO; GO:0016446; P:somatic hypermutation of immunoglobulin genes; IMP:MGI.
DR GO; GO:0016447; P:somatic recombination of immunoglobulin gene segments; IMP:MGI.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR Gene3D; 3.30.420.110; -; 1.
DR Gene3D; 3.40.1170.10; -; 1.
DR Gene3D; 3.40.50.300; -; 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 InterPro; IPR000313; PWWP_dom.
DR PANTHER; PTHR11361; PTHR11361; 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 Pfam; PF00855; PWWP; 1.
DR PIRSF; PIRSF037677; DNA_mis_repair_Msh6; 1.
DR SMART; SM00534; MUTSac; 1.
DR SMART; SM00533; MUTSd; 1.
DR SMART; SM00293; PWWP; 1.
DR SUPFAM; SSF48334; SSF48334; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF55271; SSF55271; 1.
DR PROSITE; PS00486; DNA_MISMATCH_REPAIR_2; 1.
DR PROSITE; PS50812; PWWP; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Chromosome; DNA damage; DNA repair; DNA-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome.
FT CHAIN 1..1358
FT /note="DNA mismatch repair protein Msh6"
FT /id="PRO_0000115208"
FT DOMAIN 92..154
FT /note="PWWP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00162"
FT REGION 1..87
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 197..360
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 247..273
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 325..360
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 1132..1139
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255"
FT MOD_RES 14
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 38
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 40
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 67
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 91
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 137
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 200
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 219
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 227
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 252
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 254
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 256
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 261
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 269
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 274
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 275
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 279
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 280
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 487
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 503
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 827
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 932
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT MOD_RES 1007
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P52701"
FT CONFLICT 65..66
FT /note="EA -> DG (in Ref. 1; AAC53034)"
FT /evidence="ECO:0000305"
FT CONFLICT 374..375
FT /note="PE -> QK (in Ref. 1; AAC53034)"
FT /evidence="ECO:0000305"
FT CONFLICT 754
FT /note="T -> N (in Ref. 1; AAC53034)"
FT /evidence="ECO:0000305"
FT CONFLICT 800
FT /note="D -> Y (in Ref. 1; AAC53034)"
FT /evidence="ECO:0000305"
FT CONFLICT 1227
FT /note="N -> S (in Ref. 1; AAC53034)"
FT /evidence="ECO:0000305"
FT CONFLICT 1329
FT /note="Q -> R (in Ref. 1; AAC53034)"
FT /evidence="ECO:0000305"
FT CONFLICT 1333
FT /note="E -> G (in Ref. 1; AAC53034)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1358 AA; 151084 MW; 979D289BC69E6047 CRC64;
MSRQSTLYSF FPKSPALGDT KKAAAEASRQ GAAASGASAS RGGDAAWSEA EPGSRSAAVS
ASSPEAKDLN GGLRRASSSA QAVPPSSCDF SPGDLVWAKM EGYPWWPCLV YNHPFDGTFI
RKKGKSVRVH VQFFDDSPTR GWVSKRMLKP YTGSKSKEAQ KGGHFYSSKS EILRAMQRAD
EALSKDTAER LQLAVCDEPS EPEEEEETEV HEAYLSDKSE EDNYNESEEE AQPSVQGPRR
SSRQVKKRRV ISDSESDIGG SDVEFKPDTK QEGSSDDASS GVGDSDSEDL GTFGKGAPKR
KRAMVAQGGL RRKSLKKETG SAKRATPILS ETKSTLSAFS APQNSESQTH VSGGGNDSSG
PTVWYHETLE WLKPEKRRDE HRRRPDHPEF NPTTLYVPEE FLNSCTPGMR KWWQLKSQNF
DLVIFYKVGK FYELYHMDAV IGVSELGLIF MKGNWAHSGF PEIAFGRFSD SLVQKGYKVA
RVEQTETPEM MEARCRKMAH VSKFDRVVRR EICRIITKGT QTYSVLDGDP SENYSRYLLS
LKEKEEETSG HTRVYGVCFV DTSLGKFFIG QFSDDRHCSR FRTLVAHYPP VQILFEKGNL
STETKTVLKG SLSSCLQEGL IPGSQFWDAT KTLRTLLEGG YFTGNGDSST VLPLVLKGMT
SESDSVGLTP GEESELALSA LGGIVFYLKK CLIDQELLSM ANFEEYFPLD SDTVSTVKPG
AVFTKASQRM VLDAVTLNNL EIFLNGTNGS TEGTLLERLD TCHTPFGKRL LKQWLCAPLC
SPSAISDRLD AVEDLMAVPD KVTEVADLLK KLPDLERLLS KIHNVGSPLK SQNHPDSRAI
MYEETTYSKK KIIDFLSALE GFKVMCKVSG LLEEVAGGFT SKTLKQVVTL QSKSPKGRFP
DLTAELQRWD TAFDHEKARK TGLITPKAGF DSDYDQALAD IRENEQSLLE YLDKQRSRLG
CKSIVYWGIG RNRYQLEIPE NFATRNLPEE YELKSTKKGC KRYWTKTIEK KLANLINAEE
RRDTSLKDCM RRLFCNFDKN HKDWQSAVEC IAVLDVLLCL ANYSQGGDGP MCRPEIVLPG
EDTHPFLEFK GSRHPCITKT FFGDDFIPND ILIGCEEEAE EHGKAYCVLV TGPNMGGKST
LIRQAGLLAV MAQLGCYVPA EKCRLTPVDR VFTRLGASDR IMSGESTFFV ELSETASILR
HATAHSLVLV DELGRGTATF DGTAIANAVV KELAETIKCR TLFSTHYHSL VEDYSKSVCV
RLGHMACMVE NECEDPSQET ITFLYKFIKG ACPKSYGFNA ARLANLPEEV IQKGHRKARE
FERMNQSLQL FREVCLATEK PTINGEAIHR LLALINGL
