| Structural highlights
4fmo is a 3 chain structure with sequence from Saccharomyces cerevisiae s288c. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 4fmn, 4e4w |
| Gene: | MLH1, PMS2, YMR167W, YM8520.16 (Saccharomyces cerevisiae S288c), PMS1, YNL082W, N2317 (Saccharomyces cerevisiae S288c) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[MLH1_YEAST] Required for DNA mismatch repair (MMR), correcting base-base mismatches and insertion-deletion loops (IDLs) resulting from DNA replication, DNA damage or from recombination events between non-identical sequences during meiosis. Component of different MutL heterodimers that form a ternary complex with the MutS heterodimers, which initially recognize the DNA mismatches. This complex is thought to be responsible for directing the downsteam MMR events, including strand discrimination, excision, and resynthesis. Plays a major role in maintaining the genetic stability of simple sequence repeats, the repair of heteroduplex sites present in meiotic recombination intermediates, and the promotion of meiotic crossing-over.[1] [2] [3] [EXO1_YEAST] 5'->3' double-stranded DNA exonuclease involved in mismatch repair and eventually also in mitotic recombination between direct repeats. Also has a minor role in the correction of large DNA mismatches that occur in the heteroduplex DNA during meiotic recombination at the HIS4 locus.[4] [5] [6] [7] [PMS1_YEAST] Required for DNA mismatch repair (MMR), correcting base-base mismatches and insertion-deletion loops (IDLs) resulting from DNA replication, DNA damage or from recombination events between non-identical sequences during meiosis. Component of the MutLalpha heterodimer that forms a ternary complex with the MutS heterodimers, which initially recognize the DNA mismatches. This complex is thought to be responsible for directing the downsteam MMR events, including strand discrimination, excision, and resynthesis. Plays a major role in maintaining the genetic stability of simple sequence repeats and in the repair of heteroduplex sites present in meiotic recombination intermediates.[8] [9] [10]
Publication Abstract from PubMed
Mismatch-repair factors have a prominent role in surveying eukaryotic DNA-replication fidelity and in ensuring correct meiotic recombination. These functions depend on MutL-homolog heterodimers with Mlh1. In humans, MLH1 mutations underlie half of hereditary nonpolyposis colorectal cancers (HNPCCs). Here we report crystal structures of the MutLalpha (Mlh1-Pms1 heterodimer) C-terminal domain (CTD) from Saccharomyces cerevisiae, alone and in complex with fragments derived from Mlh1 partners. These structures reveal structural rearrangements and additional domains in MutLalpha as compared to the bacterial MutL counterparts and show that the strictly conserved C terminus of Mlh1 forms part of the Pms1 endonuclease site. The structures of the ternary complexes between MutLalpha(CTD) and Exo1 or Ntg2 fragments reveal the binding mode of the MIP-box motif shared by several Mlh1 partners. Finally, the structures provide a rationale for the deleterious impact of MLH1 mutations in HNPCCs.
Structure of the MutLalpha C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site.,Gueneau E, Dherin C, Legrand P, Tellier-Lebegue C, Gilquin B, Bonnesoeur P, Londino F, Quemener C, Le Du MH, Marquez JA, Moutiez M, Gondry M, Boiteux S, Charbonnier JB Nat Struct Mol Biol. 2013 Apr;20(4):461-8. doi: 10.1038/nsmb.2511. Epub 2013 Feb , 24. PMID:23435383[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Habraken Y, Sung P, Prakash L, Prakash S. ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes. J Biol Chem. 1998 Apr 17;273(16):9837-41. PMID:9545323
- ↑ Wang TF, Kleckner N, Hunter N. Functional specificity of MutL homologs in yeast: evidence for three Mlh1-based heterocomplexes with distinct roles during meiosis in recombination and mismatch correction. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13914-9. PMID:10570173
- ↑ Argueso JL, Kijas AW, Sarin S, Heck J, Waase M, Alani E. Systematic mutagenesis of the Saccharomyces cerevisiae MLH1 gene reveals distinct roles for Mlh1p in meiotic crossing over and in vegetative and meiotic mismatch repair. Mol Cell Biol. 2003 Feb;23(3):873-86. PMID:12529393
- ↑ Tishkoff DX, Boerger AL, Bertrand P, Filosi N, Gaida GM, Kane MF, Kolodner RD. Identification and characterization of Saccharomyces cerevisiae EXO1, a gene encoding an exonuclease that interacts with MSH2. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7487-92. PMID:9207118
- ↑ Fiorentini P, Huang KN, Tishkoff DX, Kolodner RD, Symington LS. Exonuclease I of Saccharomyces cerevisiae functions in mitotic recombination in vivo and in vitro. Mol Cell Biol. 1997 May;17(5):2764-73. PMID:9111347
- ↑ Kirkpatrick DT, Ferguson JR, Petes TD, Symington LS. Decreased meiotic intergenic recombination and increased meiosis I nondisjunction in exo1 mutants of Saccharomyces cerevisiae. Genetics. 2000 Dec;156(4):1549-57. PMID:11102356
- ↑ Cotta-Ramusino C, Fachinetti D, Lucca C, Doksani Y, Lopes M, Sogo J, Foiani M. Exo1 processes stalled replication forks and counteracts fork reversal in checkpoint-defective cells. Mol Cell. 2005 Jan 7;17(1):153-9. PMID:15629726 doi:S109727650400718X
- ↑ Habraken Y, Sung P, Prakash L, Prakash S. ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes. J Biol Chem. 1998 Apr 17;273(16):9837-41. PMID:9545323
- ↑ Wang TF, Kleckner N, Hunter N. Functional specificity of MutL homologs in yeast: evidence for three Mlh1-based heterocomplexes with distinct roles during meiosis in recombination and mismatch correction. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13914-9. PMID:10570173
- ↑ Erdeniz N, Dudley S, Gealy R, Jinks-Robertson S, Liskay RM. Novel PMS1 alleles preferentially affect the repair of primer strand loops during DNA replication. Mol Cell Biol. 2005 Nov;25(21):9221-31. PMID:16227575 doi:25/21/9221
- ↑ Gueneau E, Dherin C, Legrand P, Tellier-Lebegue C, Gilquin B, Bonnesoeur P, Londino F, Quemener C, Le Du MH, Marquez JA, Moutiez M, Gondry M, Boiteux S, Charbonnier JB. Structure of the MutLalpha C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site. Nat Struct Mol Biol. 2013 Apr;20(4):461-8. doi: 10.1038/nsmb.2511. Epub 2013 Feb , 24. PMID:23435383 doi:10.1038/nsmb.2511
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