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Overview

Uniprot IDP52701
Protein NameDNA mismatch repair protein Msh6
Gene NameMSH6
OrganismHomo sapiens

Kla Sites from experimental identification

Position Flanking peptide
1014 WTKTIEKKLANLINA
13 TLYSFFPKSPALSDA
22 PALSDANKASARASR
311 VTGNGSLKRKSSRKE
317 LKRKSSRKETPSATK
324 KETPSATKQATSISS
334 TSISSETKNTLRAFS
498 MMEARCRKMAHISKY
504 RKMAHISKYDRVVRR
519 EICRIITKGTQTYSV
70 SASPPKAKNLNGGLR

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

Protein Sequence

10 MSRQSTLYSF 20 FPKSPALSDA 30 NKASARASRE 40 GGRAAAAPGA 50 SPSPGGDAAW 60 SEAGPGPRPL 70 ARSASPPKAK 80 NLNGGLRRSV 90 APAAPTSCDF 100 SPGDLVWAKM 110 EGYPWWPCLV 120 YNHPFDGTFI 130 REKGKSVRVH 140 VQFFDDSPTR 150 GWVSKRLLKP 160 YTGSKSKEAQ 170 KGGHFYSAKP 180 EILRAMQRAD 190 EALNKDKIKR 200 LELAVCDEPS 210 EPEEEEEMEV 220 GTTYVTDKSE 230 EDNEIESEEE 240 VQPKTQGSRR 250 SSRQIKKRRV 260 ISDSESDIGG 270 SDVEFKPDTK 280 EEGSSDEISS 290 GVGDSESEGL 300 NSPVKVARKR 310 KRMVTGNGSL 320 KRKSSRKETP 330 SATKQATSIS 340 SETKNTLRAF 350 SAPQNSESQA 360 HVSGGGDDSS 370 RPTVWYHETL 380 EWLKEEKRRD 390 EHRRRPDHPD 400 FDASTLYVPE 410 DFLNSCTPGM 420 RKWWQIKSQN 430 FDLVICYKVG 440 KFYELYHMDA 450 LIGVSELGLV 460 FMKGNWAHSG 470 FPEIAFGRYS 480 DSLVQKGYKV 490 ARVEQTETPE 500 MMEARCRKMA 510 HISKYDRVVR 520 REICRIITKG 530 TQTYSVLEGD 540 PSENYSKYLL 550 SLKEKEEDSS 560 GHTRAYGVCF 570 VDTSLGKFFI 580 GQFSDDRHCS 590 RFRTLVAHYP 600 PVQVLFEKGN 610 LSKETKTILK 620 SSLSCSLQEG 630 LIPGSQFWDA 640 SKTLRTLLEE 650 EYFREKLSDG 660 IGVMLPQVLK 670 GMTSESDSIG 680 LTPGEKSELA 690 LSALGGCVFY 700 LKKCLIDQEL 710 LSMANFEEYI 720 PLDSDTVSTT 730 RSGAIFTKAY 740 QRMVLDAVTL 750 NNLEIFLNGT 760 NGSTEGTLLE 770 RVDTCHTPFG 780 KRLLKQWLCA 790 PLCNHYAIND 800 RLDAIEDLMV 810 VPDKISEVVE 820 LLKKLPDLER 830 LLSKIHNVGS 840 PLKSQNHPDS 850 RAIMYEETTY 860 SKKKIIDFLS 870 ALEGFKVMCK 880 IIGIMEEVAD 890 GFKSKILKQV 900 ISLQTKNPEG 910 RFPDLTVELN 920 RWDTAFDHEK 930 ARKTGLITPK 940 AGFDSDYDQA 950 LADIRENEQS 960 LLEYLEKQRN 970 RIGCRTIVYW 980 GIGRNRYQLE 990 IPENFTTRNL 1000 PEEYELKSTK 1010 KGCKRYWTKT 1020 IEKKLANLIN 1030 AEERRDVSLK 1040 DCMRRLFYNF 1050 DKNYKDWQSA 1060 VECIAVLDVL 1070 LCLANYSRGG 1080 DGPMCRPVIL 1090 LPEDTPPFLE 1100 LKGSRHPCIT 1110 KTFFGDDFIP 1120 NDILIGCEEE 1130 EQENGKAYCV 1140 LVTGPNMGGK 1150 STLMRQAGLL 1160 AVMAQMGCYV 1170 PAEVCRLTPI 1180 DRVFTRLGAS 1190 DRIMSGESTF 1200 FVELSETASI 1210 LMHATAHSLV 1220 LVDELGRGTA 1230 TFDGTAIANA 1240 VVKELAETIK 1250 CRTLFSTHYH 1260 SLVEDYSQNV 1270 AVRLGHMACM 1280 VENECEDPSQ 1290 ETITFLYKFI 1300 KGACPKSYGF 1310 NAARLANLPE 1320 EVIQKGHRKA 1330 REFEKMNQSL 1340 RLFREVCLAS 1350 ERSTVDAEAV 1360 HKLLTLIKEL

Gene Ontology

Classification GO ID Description
Cellular Component GO:0000785 chromatin
Cellular Component GO:0032301 MutSalpha complex
Cellular Component GO:0005654 nucleoplasm
Cellular Component GO:0005634 nucleus
Molecular Function GO:0005524 ATP binding
Molecular Function GO:0008094 ATP-dependent activity, acting on DNA
Molecular Function GO:0140664 ATP-dependent DNA damage sensor activity
Molecular Function GO:0003682 chromatin binding
Molecular Function GO:0003684 damaged DNA binding
Molecular Function GO:0019899 enzyme binding
Molecular Function GO:0032137 guanine/thymine mispair binding
Molecular Function GO:0140003 histone H3K36me3 reader activity
Molecular Function GO:0030983 mismatched DNA binding
Biological Process GO:0008340 determination of adult lifespan
Biological Process GO:0006281 DNA repair
Biological Process GO:0097193 intrinsic apoptotic signaling pathway
Biological Process GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage
Biological Process GO:0045190 isotype switching
Biological Process GO:0000710 meiotic mismatch repair
Biological Process GO:0006298 mismatch repair
Biological Process GO:0045910 negative regulation of DNA recombination
Biological Process GO:0009411 response to UV
Biological Process GO:0016446 somatic hypermutation of immunoglobulin genes
Biological Process GO:0016447 somatic recombination of immunoglobulin gene segments
Biological Process GO:0007283 spermatogenesis

Reference

[1] Yang D, Yin J, Shan L, Yi X, Zhang W et al.. Identification of lysine-lactylated substrates in gastric cancer cells.. iScience 25(7):104630. 2022 Jul 15. PMID: 35800753.

[2] Yang Z, Yan C, Ma J, Peng P, Ren X et al.. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma.. Nat Metab 5(1):61-79. 2023 Jan. PMID: 36593272.

[3] Hong H, Chen X, Wang H, Gu X, Yuan Y et al.. Global profiling of protein lysine lactylation and potential target modified protein analysis in hepatocellular carcinoma.. Proteomics 23(9):e2200432. 2023 May. PMID: 36625413.

[4] He C, Zhang J, Bai X, Lu C, Zhang K. Lysine lactylation-based insight to understanding the characterization of cervical cancer.. Biochim Biophys Acta Mol Basis Dis 1870(7):167356. 2024 Oct. PMID: 39025375.

[5] Guo X, Ren X, Yan C, Huang H. Quantitative Proteomics Reveals the Role of Lysine Lactylation in Lenalidomide-Resistance in Multiple Myeloma Cells.. ACS Chem Biol 20(7):1728-1738. 2025 Jul 18. PMID: 40590393.

[6] He J, Lai T, Zhou Z, Yang H, Lei Z et al.. Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.. Sci Rep 15(1):24651. 2025 Jul 9. PMID: 40634431.

[7] Wu Q, Li Z, Gong T, Zheng X, Zhou X et al.. Porphyromonas gingivalis infection induces lysine lactylation reprogramming in human umbilical vein endothelial cells.. Front Cell Infect Microbiol 16:1706727. 2026. PMID: 41696360.