# MutS-1

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Protein family

MutS_I The crystal structure of E. coli MutS binding to DNA with an a:a mismatch Identifiers Symbol MutS_I Pfam PF01624 InterPro IPR007695 SMART MUTSd PROSITE PDOC00388 SCOP2 1ng9 / SCOPe / SUPFAM Available protein structures: PDB IPR007695 PF01624 (ECOD; PDBsum) AlphaFold IPR007695 PF01624

**MutS** is a mismatch DNA repair protein, originally described in *[Escherichia coli](/source/Escherichia_coli)*.

[Mismatch repair](/source/DNA_mismatch_repair) contributes to the overall fidelity of [DNA replication](/source/DNA_replication) and is essential for combating the [adverse effects](/source/Adverse_effect_(medicine)) of damage to the [genome](/source/Genome). It involves the correction of mismatched [base pairs](/source/Base_pairs) that have been missed by the [proofreading](/source/Proofreading_(biology)) element ([Klenow fragment](/source/Klenow_fragment)) of the DNA [polymerase](/source/Polymerase) [complex](/source/Protein_complex). The post-replicative Mismatch Repair System (MMRS) of *Escherichia coli* involves MutS (Mutator S), MutL and MutH proteins, and acts to correct [point mutations](/source/Point_mutation) or small insertion/deletion [loops](/source/Loop_(biochemistry)) produced during DNA replication.[1]

## General Function

MutS and MutL are involved in preventing [recombination](/source/Genetic_recombination) between partially [homologous](/source/Homology_(biology)) DNA [sequences](/source/Sequence_(biology)). The assembly of MMRS is initiated by MutS, which recognizes and [binds](/source/Molecular_binding) to mispaired [nucleotides](/source/Nucleotide) and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired [base](/source/Base_(chemistry)).[2] MutS can also collaborate with [methyltransferases](/source/Methyltransferase) in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch.[3] MutS exists as a dimer, where the two [monomers](/source/Monomer) have different [conformations](/source/Chemical_conformation) and form a [heterodimer](/source/Heterodimer) at the [structural](/source/Secondary_structure) level.[4] Only one monomer recognises the mismatch specifically and has [ADP](/source/Adenosine_diphosphate) bound. Non-specific major groove DNA-binding [domains](/source/Protein_domain) from both monomers embrace the DNA in a clamp-like structure. Mismatch binding [induces](/source/Regulation_of_gene_expression) ATP uptake and a [conformational change](/source/Conformational_change) in the MutS protein, resulting in a clamp that [translocates](/source/Protein_targeting) on DNA.

## Protein Structure

MutS is a modular [protein](/source/Protein) with a complex [structure](/source/Cis-regulatory_element),[5] and is composed of:

- N-terminal mismatch-recognition domain, which is similar in [structure](/source/Protein_structure) to tRNA [endonuclease](/source/Endonuclease).

- Connector domain, which is similar in [structure](/source/RNA_structure) to Holliday junction resolvase ruvC.

- Core domain, which is composed of two separate subdomains that join together to form a [helical](/source/Helix) bundle; from within the core domain, two [helices](/source/Alpha_helix) act as levers that extend towards (but do not touch) the DNA.

- Clamp domain, which is inserted between the two subdomains of the core [domain](/source/Protein_domain) at the top of the lever helices; the clamp domain has a [beta-sheet](/source/Beta-sheet) [structure](/source/Tertiary_structure).

- ATPase domain (connected to the core domain), which has a classical Walker A [motif](/source/Protein_motif).

- HTH (helix-turn-helix) domain, which is involved in [dimer](/source/Protein_dimer) contacts.

This entry represents the N-terminal domain of proteins in the MutS family of DNA mismatch repair proteins, as well as closely related proteins. The N-terminal domain of MutS is responsible for mismatch recognition and forms a 6-stranded mixed beta-sheet surrounded by three alpha-helices, which is similar to the [structure](/source/Structure) of tRNA endonuclease. [Yeast](/source/Saccharomyces_cerevisiae) MSH3,[6] bacterial proteins involved in DNA mismatch repair, and the predicted protein [product](/source/Product_(chemistry)) of the Rep-3 gene of [mouse](/source/Mus_musculus) share extensive [sequence](/source/Sequence) similarity. [Human](/source/Homo_sapiens) MSH has been implicated in non-polyposis colorectal [carcinoma](/source/Carcinoma) (HNPCC) and is a mismatch binding protein.

Biophysical studies have been conducted to investigate the binding mechanism of MutS on the mismatch sites, where the most commonly used sites of interest are G:T mismatch and T-bulge. It is observed that upon MutS binding, a 60° kink is introduced at the mismatch site. This sudden kink is recognised as an important step of the initial mismatch recognition, and in the ultimate MutS-DNA complex, the DNA is unbent.[7] In the G/T mismatch binding experiment, phenylalanine insertion has been observed as an important driving force for different MutS homologues.[8][9][10][11] In this process, the specific phenylalanine on MutS forms aromatic stacking with the unpaired thymine, and additional hydrogen bond could also be formed between thymine and the nearby residue on the MutS protein.

## Homologues and Protein Diversity

[Homologues](/source/Homology_(biology)) of MutS have been found in many [species](/source/Species) including [eukaryotes](/source/Eukaryotes) (MSH 1, 2, 3, 4, 5, and 6 proteins), [archaea](/source/Archaea) and bacteria, and together these proteins have been grouped into the MutS family. Although many of these proteins have similar activities to the E. coli MutS, there is significant diversity of function among the MutS family members. This diversity is even seen within species, where many species encode multiple MutS homologues with distinct functions.[12] Inter-species homologues may have arisen through frequent ancient [horizontal gene transfer](/source/Horizontal_gene_transfer) of MutS (and MutL) from [bacteria](/source/Zinc_dependent_phospholipase_C) to archaea and eukaryotes via endosymbiotic ancestors of [mitochondria](/source/Mitochondria) and [chloroplasts](/source/Chloroplast).[13]

## References

1. **[^](#cite_ref-pmid17919654_1-0)** Nag N, Rao BJ, Krishnamoorthy G (November 2007). "Altered dynamics of DNA bases adjacent to a mismatch: a cue for mismatch recognition by MutS". *J. Mol. Biol*. **374** (1): 39–53. [doi](/source/Doi_(identifier)):[10.1016/j.jmb.2007.08.065](https://doi.org/10.1016%2Fj.jmb.2007.08.065). [PMID](/source/PMID_(identifier)) [17919654](https://pubmed.ncbi.nlm.nih.gov/17919654).

1. **[^](#cite_ref-pmid17599803_2-0)** Miguel V, Pezza RJ, Argaraña CE (August 2007). "The C-terminal region of Escherichia coli MutS and protein oligomerization". *Biochem. Biophys. Res. Commun*. **360** (2): 412–7. [Bibcode](/source/Bibcode_(identifier)):[2007BBRC..360..412M](https://ui.adsabs.harvard.edu/abs/2007BBRC..360..412M). [doi](/source/Doi_(identifier)):[10.1016/j.bbrc.2007.06.056](https://doi.org/10.1016%2Fj.bbrc.2007.06.056). [PMID](/source/PMID_(identifier)) [17599803](https://pubmed.ncbi.nlm.nih.gov/17599803).

1. **[^](#cite_ref-pmid17951114_3-0)** Rye PT, Delaney JC, Netirojjanakul C, Sun DX, Liu JZ, Essigmann JM (February 2008). ["Mismatch repair proteins collaborate with methyltransferases in the repair of O(6)-methylguanine"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015234). *DNA Repair (Amst.)*. **7** (2): 170–6. [doi](/source/Doi_(identifier)):[10.1016/j.dnarep.2007.09.003](https://doi.org/10.1016%2Fj.dnarep.2007.09.003). [PMC](/source/PMC_(identifier)) [3015234](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3015234). [PMID](/source/PMID_(identifier)) [17951114](https://pubmed.ncbi.nlm.nih.gov/17951114).

1. **[^](#cite_ref-pmid17426027_4-0)** Mendillo ML, Putnam CD, Kolodner RD (June 2007). ["Escherichia coli MutS tetramerization domain structure reveals that stable dimers but not tetramers are essential for DNA mismatch repair in vivo"](https://doi.org/10.1074%2Fjbc.M700858200). *J. Biol. Chem*. **282** (22): 16345–54. [doi](/source/Doi_(identifier)):[10.1074/jbc.M700858200](https://doi.org/10.1074%2Fjbc.M700858200). [PMID](/source/PMID_(identifier)) [17426027](https://pubmed.ncbi.nlm.nih.gov/17426027).

1. **[^](#cite_ref-pmid11048711_5-0)** Lamers MH, Perrakis A, Enzlin JH, Winterwerp HH, de Wind N, Sixma TK (October 2000). "The crystal structure of DNA mismatch repair protein MutS binding to a G x T mismatch". *Nature*. **407** (6805): 711–7. [Bibcode](/source/Bibcode_(identifier)):[2000Natur.407..711L](https://ui.adsabs.harvard.edu/abs/2000Natur.407..711L). [doi](/source/Doi_(identifier)):[10.1038/35037523](https://doi.org/10.1038%2F35037523). [PMID](/source/PMID_(identifier)) [11048711](https://pubmed.ncbi.nlm.nih.gov/11048711). [S2CID](/source/S2CID_(identifier)) [4431622](https://api.semanticscholar.org/CorpusID:4431622).

1. **[^](#cite_ref-pmid8510668_6-0)** New L, Liu K, Crouse GF (May 1993). "The yeast gene MSH3 defines a new class of eukaryotic MutS homologues". *Mol. Gen. Genet*. **239** (1–2): 97–108. [doi](/source/Doi_(identifier)):[10.1007/BF00281607](https://doi.org/10.1007%2FBF00281607). [PMID](/source/PMID_(identifier)) [8510668](https://pubmed.ncbi.nlm.nih.gov/8510668). [S2CID](/source/S2CID_(identifier)) [24113631](https://api.semanticscholar.org/CorpusID:24113631).

1. **[^](#cite_ref-7)** Wang, Hong; Yang, Yong; Schofield, Mark J.; Du, Chunwei; Fridman, Yonatan; Lee, Susan D.; Larson, Erik D.; Drummond, James T.; Alani, Eric; Hsieh, Peggy; Erie, Dorothy A. (2003-12-09). ["DNA bending and unbending by MutS govern mismatch recognition and specificity"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC299810). *Proceedings of the National Academy of Sciences*. **100** (25): 14822–14827. [Bibcode](/source/Bibcode_(identifier)):[2003PNAS..10014822W](https://ui.adsabs.harvard.edu/abs/2003PNAS..10014822W). [doi](/source/Doi_(identifier)):[10.1073/pnas.2433654100](https://doi.org/10.1073%2Fpnas.2433654100). [PMC](/source/PMC_(identifier)) [299810](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC299810). [PMID](/source/PMID_(identifier)) [14634210](https://pubmed.ncbi.nlm.nih.gov/14634210).

1. **[^](#cite_ref-8)** Malkov, Vladislav A.; Biswas, Indranil; Camerini-Otero, R. Daniel; Hsieh, Peggy (1997-09-19). ["Photocross-linking of the NH2-terminal Region of Taq MutS Protein to the Major Groove of a Heteroduplex DNA *"](https://doi.org/10.1074%2Fjbc.272.38.23811). *Journal of Biological Chemistry*. **272** (38): 23811–23817. [doi](/source/Doi_(identifier)):[10.1074/jbc.272.38.23811](https://doi.org/10.1074%2Fjbc.272.38.23811). [ISSN](/source/ISSN_(identifier)) [0021-9258](https://search.worldcat.org/issn/0021-9258). [PMID](/source/PMID_(identifier)) [9295328](https://pubmed.ncbi.nlm.nih.gov/9295328).

1. **[^](#cite_ref-9)** Yamamoto, A. (2000-09-15). ["Requirement for Phe36 for DNA binding and mismatch repair by Escherichia coli MutS protein"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC110738). *Nucleic Acids Research*. **28** (18): 3564–3569. [doi](/source/Doi_(identifier)):[10.1093/nar/28.18.3564](https://doi.org/10.1093%2Fnar%2F28.18.3564). [PMC](/source/PMC_(identifier)) [110738](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC110738). [PMID](/source/PMID_(identifier)) [10982877](https://pubmed.ncbi.nlm.nih.gov/10982877).

1. **[^](#cite_ref-10)** Bowers, Jayson; Sokolsky, Tanya; Quach, Tony; Alani, Eric (1999-06-04). ["A Mutation in the MSH6 Subunit of the Saccharomyces cerevisiae MSH2-MSH6 Complex Disrupts Mismatch Recognition *"](https://doi.org/10.1074%2Fjbc.274.23.16115). *Journal of Biological Chemistry*. **274** (23): 16115–16125. [doi](/source/Doi_(identifier)):[10.1074/jbc.274.23.16115](https://doi.org/10.1074%2Fjbc.274.23.16115). [ISSN](/source/ISSN_(identifier)) [0021-9258](https://search.worldcat.org/issn/0021-9258). [PMID](/source/PMID_(identifier)) [10347163](https://pubmed.ncbi.nlm.nih.gov/10347163).

1. **[^](#cite_ref-11)** Dufner, Patrick; Marra, Giancarlo; Räschle, Markus; Jiricny, Josef (2000-11-24). ["Mismatch Recognition and DNA-dependent Stimulation of the ATPase Activity of hMutSα Is Abolished by a Single Mutation in the hMSH6 Subunit*"](https://doi.org/10.1074%2Fjbc.M005987200). *Journal of Biological Chemistry*. **275** (47): 36550–36555. [doi](/source/Doi_(identifier)):[10.1074/jbc.M005987200](https://doi.org/10.1074%2Fjbc.M005987200). [ISSN](/source/ISSN_(identifier)) [0021-9258](https://search.worldcat.org/issn/0021-9258). [PMID](/source/PMID_(identifier)) [10938287](https://pubmed.ncbi.nlm.nih.gov/10938287).

1. **[^](#cite_ref-pmid9722651_12-0)** Eisen JA (September 1998). ["A phylogenomic study of the MutS family of proteins"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC147835). *Nucleic Acids Res*. **26** (18): 4291–300. [doi](/source/Doi_(identifier)):[10.1093/nar/26.18.4291](https://doi.org/10.1093%2Fnar%2F26.18.4291). [PMC](/source/PMC_(identifier)) [147835](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC147835). [PMID](/source/PMID_(identifier)) [9722651](https://pubmed.ncbi.nlm.nih.gov/9722651).

1. **[^](#cite_ref-pmid17965091_13-0)** Lin Z, Nei M, Ma H (2007). ["The origins and early evolution of DNA mismatch repair genes--multiple horizontal gene transfers and co-evolution"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190696). *Nucleic Acids Res*. **35** (22): 7591–603. [doi](/source/Doi_(identifier)):[10.1093/nar/gkm921](https://doi.org/10.1093%2Fnar%2Fgkm921). [PMC](/source/PMC_(identifier)) [2190696](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190696). [PMID](/source/PMID_(identifier)) [17965091](https://pubmed.ncbi.nlm.nih.gov/17965091).

This article incorporates text from the public domain [Pfam](/source/Pfam) and [InterPro](/source/InterPro): [IPR007695](https://www.ebi.ac.uk/interpro/entry/IPR007695)

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Adapted from the Wikipedia article [MutS-1](https://en.wikipedia.org/wiki/MutS-1) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/MutS-1?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.