P54276 (MSH6_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
DNA mismatch repair protein Msh6

Alternative name(s):
G/T mismatch-binding protein
Short name=GTBP
Short name=GTMBP
MutS-alpha 160 kDa subunit
p160

Gene names

Name:	Msh6
Synonyms:	Gtmbp

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1358 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction By similarity.
Subunit structure	Heterodimer consisting of MSH2-MSH6 (MutS alpha). Forms a ternary complex with MutL alpha (MLH1-PMS1). Interacts with EXO1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with ATR By similarity.
Subcellular location	Nucleus By similarity. Chromosome By similarity. Note: Associates with H3K36me3 via its PWWP domain By similarity.
Domain	The PWWP domain specifically recognizes and binds trimethylated 'Lys-36' of histone H3 (H3K36me3) By similarity.
Post-translational modification	Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway By similarity.
Sequence similarities	Belongs to the DNA mismatch repair MutS family. Contains 1 PWWP domain.

Ontologies

Keywords
Biological process	DNA damage DNA repair
Cellular component	Chromosome Nucleus
Ligand	ATP-binding DNA-binding Nucleotide-binding
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	determination of adult lifespan Inferred from mutant phenotype PubMed 10545954Ref.2. Source: MGI intrinsic apoptotic signaling pathway in response to DNA damage Inferred from mutant phenotype PubMed 15324697. Source: MGI isotype switching Inferred from mutant phenotype PubMed 16618598. Source: MGI maintenance of DNA repeat elements Inferred from Biological aspect of Ancestor. Source: RefGenome meiotic mismatch repair Inferred from Biological aspect of Ancestor. Source: RefGenome negative regulation of DNA recombination Inferred from mutant phenotype PubMed 10545954. Source: MGI positive regulation of helicase activity Inferred from electronic annotation. Source: Ensembl reciprocal meiotic recombination Inferred from Biological aspect of Ancestor. Source: RefGenome response to UV Inferred from mutant phenotype PubMed 14632208. Source: MGI somatic hypermutation of immunoglobulin genes Inferred from mutant phenotype PubMed 10662804PubMed 15238604PubMed 16618598. Source: MGI
Cellular_component	MutSalpha complex Inferred from direct assay PubMed 16713580. Source: MGI nuclear chromatin Inferred from direct assay PubMed 16618598. Source: MGI
Molecular_function	ADP binding Inferred from electronic annotation. Source: Ensembl ATP binding Inferred from electronic annotation. Source: UniProtKB-KW DNA-dependent ATPase activity Inferred from Biological aspect of Ancestor. Source: RefGenome chromatin binding Inferred from direct assay PubMed 16618598. Source: MGI damaged DNA binding Inferred from mutant phenotype PubMed 10545954. Source: MGI four-way junction DNA binding Inferred from Biological aspect of Ancestor. Source: RefGenome guanine/thymine mispair binding Inferred from direct assay PubMed 15324697. Source: MGI magnesium ion binding Inferred from electronic annotation. Source: Ensembl methylated histone residue binding Inferred from sequence or structural similarity. Source: UniProtKB oxidized purine DNA binding Inferred from electronic annotation. Source: Ensembl single base insertion or deletion binding Inferred from Biological aspect of Ancestor. Source: RefGenome single guanine insertion binding Inferred from electronic annotation. Source: Ensembl single thymine insertion binding Inferred from electronic annotation. Source: Ensembl
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1358	1358	DNA mismatch repair protein Msh6		PRO_0000115208
Regions
	Domain	92 – 154	63	PWWP
	Nucleotide binding	1132 – 1139	8	ATP Potential
	Compositional bias	201 – 209	9	Poly-Glu
Amino acid modifications
	Modified residue	14	1	Phosphoserine By similarity
	Modified residue	38	1	Phosphoserine By similarity
	Modified residue	40	1	Phosphoserine By similarity
	Modified residue	67	1	N6-acetyllysine By similarity
	Modified residue	91	1	Phosphoserine By similarity
	Modified residue	137	1	Phosphoserine By similarity
	Modified residue	200	1	Phosphoserine By similarity
	Modified residue	219	1	Phosphoserine By similarity
	Modified residue	227	1	Phosphoserine By similarity
	Modified residue	252	1	Phosphoserine By similarity
	Modified residue	254	1	Phosphoserine By similarity
	Modified residue	256	1	Phosphoserine By similarity
	Modified residue	261	1	Phosphoserine Ref.5
	Modified residue	269	1	Phosphothreonine By similarity
	Modified residue	274	1	Phosphoserine By similarity
	Modified residue	275	1	Phosphoserine By similarity
	Modified residue	279	1	Phosphoserine By similarity
	Modified residue	280	1	Phosphoserine By similarity
	Modified residue	503	1	N6-acetyllysine By similarity
	Modified residue	827	1	Phosphoserine By similarity
Experimental info
	Sequence conflict	65 – 66	2	EA → DG in AAC53034. Ref.1
	Sequence conflict	374 – 375	2	PE → QK in AAC53034. Ref.1
	Sequence conflict	754	1	T → N in AAC53034. Ref.1
	Sequence conflict	800	1	D → Y in AAC53034. Ref.1
	Sequence conflict	1227	1	N → S in AAC53034. Ref.1
	Sequence conflict	1329	1	Q → R in AAC53034. Ref.1
	Sequence conflict	1333	1	E → G in AAC53034. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P54276 [UniParc]. Last modified July 27, 2011. Version 3. Checksum: 979D289BC69E6047	FASTA	1,358	151,084
	10 20 30 40 50 60 MSRQSTLYSF FPKSPALGDT KKAAAEASRQ GAAASGASAS RGGDAAWSEA EPGSRSAAVS 70 80 90 100 110 120 ASSPEAKDLN GGLRRASSSA QAVPPSSCDF SPGDLVWAKM EGYPWWPCLV YNHPFDGTFI 130 140 150 160 170 180 RKKGKSVRVH VQFFDDSPTR GWVSKRMLKP YTGSKSKEAQ KGGHFYSSKS EILRAMQRAD 190 200 210 220 230 240 EALSKDTAER LQLAVCDEPS EPEEEEETEV HEAYLSDKSE EDNYNESEEE AQPSVQGPRR 250 260 270 280 290 300 SSRQVKKRRV ISDSESDIGG SDVEFKPDTK QEGSSDDASS GVGDSDSEDL GTFGKGAPKR 310 320 330 340 350 360 KRAMVAQGGL RRKSLKKETG SAKRATPILS ETKSTLSAFS APQNSESQTH VSGGGNDSSG 370 380 390 400 410 420 PTVWYHETLE WLKPEKRRDE HRRRPDHPEF NPTTLYVPEE FLNSCTPGMR KWWQLKSQNF 430 440 450 460 470 480 DLVIFYKVGK FYELYHMDAV IGVSELGLIF MKGNWAHSGF PEIAFGRFSD SLVQKGYKVA 490 500 510 520 530 540 RVEQTETPEM MEARCRKMAH VSKFDRVVRR EICRIITKGT QTYSVLDGDP SENYSRYLLS 550 560 570 580 590 600 LKEKEEETSG HTRVYGVCFV DTSLGKFFIG QFSDDRHCSR FRTLVAHYPP VQILFEKGNL 610 620 630 640 650 660 STETKTVLKG SLSSCLQEGL IPGSQFWDAT KTLRTLLEGG YFTGNGDSST VLPLVLKGMT 670 680 690 700 710 720 SESDSVGLTP GEESELALSA LGGIVFYLKK CLIDQELLSM ANFEEYFPLD SDTVSTVKPG 730 740 750 760 770 780 AVFTKASQRM VLDAVTLNNL EIFLNGTNGS TEGTLLERLD TCHTPFGKRL LKQWLCAPLC 790 800 810 820 830 840 SPSAISDRLD AVEDLMAVPD KVTEVADLLK KLPDLERLLS KIHNVGSPLK SQNHPDSRAI 850 860 870 880 890 900 MYEETTYSKK KIIDFLSALE GFKVMCKVSG LLEEVAGGFT SKTLKQVVTL QSKSPKGRFP 910 920 930 940 950 960 DLTAELQRWD TAFDHEKARK TGLITPKAGF DSDYDQALAD IRENEQSLLE YLDKQRSRLG 970 980 990 1000 1010 1020 CKSIVYWGIG RNRYQLEIPE NFATRNLPEE YELKSTKKGC KRYWTKTIEK KLANLINAEE 1030 1040 1050 1060 1070 1080 RRDTSLKDCM RRLFCNFDKN HKDWQSAVEC IAVLDVLLCL ANYSQGGDGP MCRPEIVLPG 1090 1100 1110 1120 1130 1140 EDTHPFLEFK GSRHPCITKT FFGDDFIPND ILIGCEEEAE EHGKAYCVLV TGPNMGGKST 1150 1160 1170 1180 1190 1200 LIRQAGLLAV MAQLGCYVPA EKCRLTPVDR VFTRLGASDR IMSGESTFFV ELSETASILR 1210 1220 1230 1240 1250 1260 HATAHSLVLV DELGRGTATF DGTAIANAVV KELAETIKCR TLFSTHYHSL VEDYSKSVCV 1270 1280 1290 1300 1310 1320 RLGHMACMVE NECEDPSQET ITFLYKFIKG ACPKSYGFNA ARLANLPEEV IQKGHRKARE 1330 1340 1350 FERMNQSLQL FREVCLATEK PTINGEAIHR LLALINGL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"cDNA sequence, map, and expression of the murine homolog of GTBP, a DNA mismatch repair gene." Corradi A., Croci L., Stayton C.L., Gulisano M., Boncinelli E., Consalez G.G. Genomics 36:288-295(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Mutation in the mismatch repair gene Msh6 causes cancer susceptibility." Edelmann W., Yang K., Umar A., Heyer J., Lau K., Fan K., Liedtke W., Cohen P., Kane M.K., Lipford J.R., Yu N., Crouse G.F., Pollard J.W., Kunkel T., Lipkin M., Kolodner R., Kucherlapati R. Cell 91:467-477(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: 129/Ola.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Mammary tumor.
[4]	Donohue P.J., Feng S.L.Y., Alberts G.F., Guo Y., Peifley K.A., Hsu D.K.W., Winkles J.A. Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 375-425 AND 1001-1050.
[5]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-261, MASS SPECTROMETRY. Tissue: Liver.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U42190 mRNA. Translation: AAC53034.1. AF031087, AF031085, AF031086 Genomic DNA. Translation: AAB88445.1. BC051160 mRNA. Translation: AAH51160.1. BC051634 mRNA. Translation: AAH51634.1. U61388 mRNA. Translation: AAB39930.1. U61389 mRNA. Translation: AAB39931.1.
RefSeq	NP_034960.1. NM_010830.2.
UniGene	Mm.18210.
3D structure databases
ProteinModelPortal	P54276.
SMR	P54276. Positions 65-201, 361-1333.
ModBase	Search...
MobiDB	Search...
Protein-protein interaction databases
BioGrid	201528. 4 interactions.
IntAct	P54276. 5 interactions.
PTM databases
PhosphoSite	P54276.
Proteomic databases
PaxDb	P54276.
PRIDE	P54276.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000005503; ENSMUSP00000005503; ENSMUSG00000005370.
GeneID	17688.
KEGG	mmu:17688.
UCSC	uc008dvd.2. mouse.
Organism-specific databases
CTD	2956.
MGI	MGI:1343961. Msh6.
Phylogenomic databases
eggNOG	COG0249.
GeneTree	ENSGT00550000075024.
HOGENOM	HOG000243127.
HOVERGEN	HBG000101.
InParanoid	Q6GTK8.
KO	K08737.
OMA	HMDAVIG.
OrthoDB	EOG7K9K27.
TreeFam	TF105842.
Gene expression databases
ArrayExpress	P54276.
Bgee	P54276.
CleanEx	MM_MSH6.
Genevestigator	P54276.
Family and domain databases
Gene3D	3.40.1170.10. 1 hit.
InterPro	IPR017261. DNA_mismatch_repair_Msh6. IPR015536. DNA_mismatch_repair_MSH6_C. IPR007695. DNA_mismatch_repair_MutS-lik_N. IPR000432. DNA_mismatch_repair_MutS_C. IPR007861. DNA_mismatch_repair_MutS_clamp. IPR007696. DNA_mismatch_repair_MutS_core. IPR016151. DNA_mismatch_repair_MutS_N. IPR007860. DNA_mmatch_repair_MutS_con_dom. IPR027417. P-loop_NTPase. IPR000313. PWWP_dom. [Graphical view]
PANTHER	PTHR11361:SF31. PTHR11361:SF31. 1 hit.
Pfam	PF01624. MutS_I. 1 hit. PF05188. MutS_II. 1 hit. PF05192. MutS_III. 1 hit. PF05190. MutS_IV. 1 hit. PF00488. MutS_V. 1 hit. PF00855. PWWP. 1 hit. [Graphical view]
PIRSF	PIRSF037677. DNA_mis_repair_Msh6. 1 hit.
SMART	SM00534. MUTSac. 1 hit. SM00533. MUTSd. 1 hit. SM00293. PWWP. 1 hit. [Graphical view]
SUPFAM	SSF48334. SSF48334. 1 hit. SSF52540. SSF52540. 1 hit. SSF55271. SSF55271. 1 hit.
PROSITE	PS00486. DNA_MISMATCH_REPAIR_2. 1 hit. PS50812. PWWP. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	MSH6. mouse.
NextBio	292264.
PRO	P54276.
SOURCE	Search...

Entry information

Entry name

MSH6_MOUSE

Accession

Primary (citable) accession number: P54276
Secondary accession number(s): O54710, Q6GTK8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	July 27, 2011
Last modified:	February 19, 2014
This is version 102 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program