Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

P38920 (MLH1_YEAST) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
DNA mismatch repair protein MLH1
Alternative name(s):
MutL protein homolog 1
Post meiotic segregation protein 2
Gene names
Name:MLH1
Synonyms:PMS2
Ordered Locus Names:YMR167W
ORF Names:YM8520.16
OrganismSaccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) [Reference proteome]
Taxonomic identifier559292 [NCBI]
Taxonomic lineageEukaryotaFungiDikaryaAscomycotaSaccharomycotinaSaccharomycetesSaccharomycetalesSaccharomycetaceaeSaccharomyces

Protein attributes

Sequence length769 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.7 Ref.8 Ref.12

Subunit structure

Heterodimer of MLH1 and PMS1, called MutLalpha, which is the major MMR MutL activity correcting base-base mismatches as well as IDLs. The heterodimer binds double strand DNA independently of a mismatch with positive cooperativity and has more than one DNA binding site. Forms a ternary complex with either the MSH2-MSH6 (MutSalpha) or the MSH2-MSH3 heterodimer (MutSbeta), which recognize and bind to mismatch DNA. Ternary complex formation is promoted by ATP binding. Heterodimer of MLH1 and MLH3, called MutLbeta, which is involved in correction of a specific subset of IDLs when associated with MutSbeta. Heterodimer of MLH1 and MLH2. Ref.7

Subcellular location

Nucleus Ref.13.

Miscellaneous

Present with 319 molecules/cell in log phase SD medium.

Sequence similarities

Belongs to the DNA mismatch repair MutL/HexB family.

Biophysicochemical properties

Kinetic parameters:

KM=69 µM for ATP Ref.11

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 769769DNA mismatch repair protein MLH1
PRO_0000178008

Regions

Region1 – 335335DNA- and ATP-binding
Region501 – 756256Interaction with PMS1

Amino acid modifications

Modified residue4411Phosphoserine; by ATM or ATR Ref.16

Natural variations

Natural variant2401S → R in strain: SK1. Ref.2
Natural variant2421D → E in strain: YJM326 and YJM339. Ref.2
Natural variant2711L → P in strain: EAY1066, EAY1068, M2-8, M7-8, M5-7, SK1, YJM269, YJM280, YJM320, YJM326, YJM339 and YJM627. Ref.2
Natural variant3091P → L in strain: M2-8. Ref.2
Natural variant3211E → D in strain: EAY1066. Ref.2
Natural variant3331E → K in strain: SK1. Ref.2
Natural variant3751A → T in strain: YJM339. Ref.2
Natural variant4521S → G in strain: EAY1068, M2-8, M7-8, M5-7, YJM269 and YJM627. Ref.2
Natural variant4651D → N in strain: EAY1066 and YJM280. Ref.2
Natural variant4701P → S in strain: YJM339. Ref.2
Natural variant6071L → F in strain: EAY1068, M2-8, M7-8, M5-7 and YJM627. Ref.2
Natural variant6781D → N in strain: SK1, YJM320 and YJM339. Ref.2
Natural variant7031P → L in strain: SK1, YJM320 and YJM339. Ref.2
Natural variant7611D → G in strain: EAY1066, EAY1068, M2-8, M7-8, M5-7, SK1, YJM145, YJM269, YJM320, YJM339 and YJM627; forms a non-functional heterodimer with PMS1 from strain S288c, resulting in an accumulation of mutations in spore progeny of crosses between these strains. Ref.2

Experimental info

Mutagenesis311E → A: Reduces ATPase activity by 98%. Displays 3300-fold increase in spontaneous mutation accumulation. Ref.9 Ref.11
Mutagenesis351N → A: Abolishes ATP binding, reducing ATPase activity by 95%. Displays 9800-fold increase in spontaneous mutation accumulation. Ref.11
Mutagenesis411A → F: Defective in a mismatch repair assay. Abolishes heterodimer formation. Displays an increases spontaneous mutation accumulation. Ref.5 Ref.6
Mutagenesis411A → G: Reduces heterodimer formation. Displays an weak increase in spontaneous mutation accumulation. Ref.5 Ref.6
Mutagenesis411A → S: Fully functional in a mismatch repair assay. Ref.5 Ref.6
Mutagenesis641G → R: Defective in a mismatch repair assay. Ref.5
Mutagenesis651I → N: Defective in a mismatch repair assay. Ref.5
Mutagenesis961F → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. Ref.6
Mutagenesis971R → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. Ref.6
Mutagenesis981G → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. Ref.6 Ref.9
Mutagenesis981G → V: Abolishes heterodimer formation. Displays an increase in spontaneous mutation accumulation. Ref.6 Ref.9
Mutagenesis991E → K: Defective in a mismatch repair assay. Ref.5
Mutagenesis1041I → R: Defective in a mismatch repair assay. Ref.5
Mutagenesis1141T → R: Defective in a mismatch repair assay. Ref.5
Mutagenesis2141R → C: Partially defective in a mismatch repair assay. Ref.5
Mutagenesis2161V → I: Fully functional in a mismatch repair assay. Ref.5
Mutagenesis2651R → C: Partially defective in a mismatch repair assay. Ref.5
Mutagenesis2651R → H: Partially defective in a mismatch repair assay. Ref.5
Mutagenesis2731R → E: Strongly reduces DNA-binding and displays 12000-fold increase in spontaneous mutation accumulation; when associated with E-274. Ref.15
Mutagenesis2741R → E: Reduces DNA-binding and displays a 1700-fold increase in spontaneous mutation accumulation. Strongly reduces DNA-binding and displays 12000-fold increase in spontaneous mutation accumulation; when associated with E-273. Ref.15
Mutagenesis3261I → A: Partially defective in a mismatch repair assay. Ref.5
Mutagenesis3261I → V: Fully functional in a mismatch repair assay. Ref.5
Mutagenesis5521Q → L: Defective in a mismatch repair assay. Ref.5
Mutagenesis6721R → P: Defective in a mismatch repair assay. Ref.5
Mutagenesis6941A → T: Fully functional in a mismatch repair assay. Ref.5
Mutagenesis7641K → E: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. Ref.6
Mutagenesis7641K → R: No effect. Ref.6
Mutagenesis7661F → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. Ref.6
Mutagenesis7671E → D: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. Ref.6
Mutagenesis7691C → A: No effect. Ref.6
Mutagenesis7691C → S: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. Ref.6
Sequence conflict2581P → L in AAA16835. Ref.1
Sequence conflict2881N → F in AAA16835. Ref.1
Sequence conflict7081S → L in AAA16835. Ref.1

Secondary structure

....................................... 769
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P38920 [UniParc].

Last modified October 1, 1996. Version 2.
Checksum: B2DBB31DE3943171

FASTA76987,062
        10         20         30         40         50         60 
MSLRIKALDA SVVNKIAAGE IIISPVNALK EMMENSIDAN ATMIDILVKE GGIKVLQITD 

        70         80         90        100        110        120 
NGSGINKADL PILCERFTTS KLQKFEDLSQ IQTYGFRGEA LASISHVARV TVTTKVKEDR 

       130        140        150        160        170        180 
CAWRVSYAEG KMLESPKPVA GKDGTTILVE DLFFNIPSRL RALRSHNDEY SKILDVVGRY 

       190        200        210        220        230        240 
AIHSKDIGFS CKKFGDSNYS LSVKPSYTVQ DRIRTVFNKS VASNLITFHI SKVEDLNLES 

       250        260        270        280        290        300 
VDGKVCNLNF ISKKSISPIF FINNRLVTCD LLRRALNSVY SNYLPKGNRP FIYLGIVIDP 

       310        320        330        340        350        360 
AAVDVNVHPT KREVRFLSQD EIIEKIANQL HAELSAIDTS RTFKASSIST NKPESLIPFN 

       370        380        390        400        410        420 
DTIESDRNRK SLRQAQVVEN SYTTANSQLR KAKRQENKLV RIDASQAKIT SFLSSSQQFN 

       430        440        450        460        470        480 
FEGSSTKRQL SEPKVTNVSH SQEAEKLTLN ESEQPRDANT INDNDLKDQP KKKQKLGDYK 

       490        500        510        520        530        540 
VPSIADDEKN ALPISKDGYI RVPKERVNVN LTSIKKLREK VDDSIHRELT DIFANLNYVG 

       550        560        570        580        590        600 
VVDEERRLAA IQHDLKLFLI DYGSVCYELF YQIGLTDFAN FGKINLQSTN VSDDIVLYNL 

       610        620        630        640        650        660 
LSEFDELNDD ASKEKIISKI WDMSSMLNEY YSIELVNDGL DNDLKSVKLK SLPLLLKGYI 

       670        680        690        700        710        720 
PSLVKLPFFI YRLGKEVDWE DEQECLDGIL REIALLYIPD MVPKVDTSDA SLSEDEKAQF 

       730        740        750        760 
INRKEHISSL LEHVLFPCIK RRFLAPRHIL KDVVEIANLP DLYKVFERC 

« Hide

References

« Hide 'large scale' references
[1]"Dual requirement in yeast DNA mismatch repair for MLH1 and PMS1, two homologs of the bacterial mutL gene."
Prolla T.A., Christie D.-M., Liskay R.M.
Mol. Cell. Biol. 14:407-415(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]"Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair."
Heck J.A., Argueso J.L., Gemici Z., Reeves R.G., Bernard A., Aquadro C.F., Alani E.
Proc. Natl. Acad. Sci. U.S.A. 103:3256-3261(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-240; GLU-242; PRO-271; LEU-309; ASP-321; LYS-333; THR-375; GLY-452; ASN-465; SER-470; PHE-607; ASN-678; LEU-703 AND GLY-761.
Strain: ATCC 200060 / W303, EAY1066, EAY1068, M2-8, M5-7, M7-8, SK1, YJM 145, YJM 269, YJM 280, YJM 320, YJM 326, YJM 339 and YJM 627.
[3]"The nucleotide sequence of Saccharomyces cerevisiae chromosome XIII."
Bowman S., Churcher C.M., Badcock K., Brown D., Chillingworth T., Connor R., Dedman K., Devlin K., Gentles S., Hamlin N., Hunt S., Jagels K., Lye G., Moule S., Odell C., Pearson D., Rajandream M.A., Rice P. expand/collapse author list , Skelton J., Walsh S.V., Whitehead S., Barrell B.G.
Nature 387:90-93(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: ATCC 204508 / S288c.
[4]Saccharomyces Genome Database
Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases
Cited for: GENOME REANNOTATION.
Strain: ATCC 204508 / S288c.
[5]"Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae."
Ellison A.R., Lofing J., Bitter G.A.
Hum. Mol. Genet. 10:1889-1900(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ALA-41; GLY-64; ILE-65; GLU-99; ILE-104; THR-114; ARG-214; VAL-216; ARG-265; ILE-326; GLN-552; ARG-672 AND ALA-694.
[6]"Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch repair proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations."
Pang Q., Prolla T.A., Liskay R.M.
Mol. Cell. Biol. 17:4465-4473(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PMS1, MUTAGENESIS OF ALA-41; PHE-96; ARG-97; GLY-98; LYS-764; PHE-766; GLU-767 AND CYS-769.
[7]"ATP-dependent assembly of a ternary complex consisting of a DNA mismatch and the yeast MSH2-MSH6 and MLH1-PMS1 protein complexes."
Habraken Y., Sung P., Prakash L., Prakash S.
J. Biol. Chem. 273:9837-9841(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBUNIT.
[8]"Functional specificity of MutL homologs in yeast: evidence for three Mlh1-based heterocomplexes with distinct roles during meiosis in recombination and mismatch correction."
Wang T.-F., Kleckner N., Hunter N.
Proc. Natl. Acad. Sci. U.S.A. 96:13914-13919(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MLH2; MLH3 AND PMS1.
[9]"Functional studies on the candidate ATPase domains of Saccharomyces cerevisiae MutLalpha."
Tran P.T., Liskay R.M.
Mol. Cell. Biol. 20:6390-6398(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PMS1, ATP-BINDING, MUTAGENESIS OF GLU-31 AND GLY-98.
[10]"DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers."
Drotschmann K., Hall M.C., Shcherbakova P.V., Wang H., Erie D.A., Brownewell F.R., Kool E.T., Kunkel T.A.
Biol. Chem. 383:969-975(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: DNA-BINDING.
[11]"Differential ATP binding and intrinsic ATP hydrolysis by amino-terminal domains of the yeast Mlh1 and Pms1 proteins."
Hall M.C., Shcherbakova P.V., Kunkel T.A.
J. Biol. Chem. 277:3673-3679(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: ATP-BINDING, MUTAGENESIS OF GLU-31 AND ASN-35, BIOPHYSICOCHEMICAL PROPERTIES.
[12]"Systematic mutagenesis of the Saccharomyces cerevisiae MLH1 gene reveals distinct roles for Mlh1p in meiotic crossing over and in vegetative and meiotic mismatch repair."
Argueso J.L., Kijas A.W., Sarin S., Heck J.A., Waase M., Alani E.
Mol. Cell. Biol. 23:873-886(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS.
[13]"Global analysis of protein localization in budding yeast."
Huh W.-K., Falvo J.V., Gerke L.C., Carroll A.S., Howson R.W., Weissman J.S., O'Shea E.K.
Nature 425:686-691(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
[14]"Global analysis of protein expression in yeast."
Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N., O'Shea E.K., Weissman J.S.
Nature 425:737-741(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
[15]"DNA binding by yeast Mlh1 and Pms1: implications for DNA mismatch repair."
Hall M.C., Shcherbakova P.V., Fortune J.M., Borchers C.H., Dial J.M., Tomer K.B., Kunkel T.A.
Nucleic Acids Res. 31:2025-2034(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: DNA-BINDING, MUTAGENESIS OF ARG-273 AND ARG-274.
[16]"A multidimensional chromatography technology for in-depth phosphoproteome analysis."
Albuquerque C.P., Smolka M.B., Payne S.H., Bafna V., Eng J., Zhou H.
Mol. Cell. Proteomics 7:1389-1396(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-441, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]"Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution."
Holt L.J., Tuch B.B., Villen J., Johnson A.D., Gygi S.P., Morgan D.O.
Science 325:1682-1686(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U07187 Unassigned DNA. Translation: AAA16835.1.
DQ356633 Genomic DNA. Translation: ABC86937.1.
DQ356634 Genomic DNA. Translation: ABC86938.1.
DQ356635 Genomic DNA. Translation: ABC86939.1.
DQ356636 Genomic DNA. Translation: ABC86940.1.
DQ356637 Genomic DNA. Translation: ABC86941.1.
DQ356638 Genomic DNA. Translation: ABC86942.1.
DQ356639 Genomic DNA. Translation: ABC86943.1.
DQ356640 Genomic DNA. Translation: ABC86944.1.
DQ356641 Genomic DNA. Translation: ABC86945.1.
DQ356642 Genomic DNA. Translation: ABC86946.1.
DQ356643 Genomic DNA. Translation: ABC86947.1.
DQ356644 Genomic DNA. Translation: ABC86948.1.
DQ356645 Genomic DNA. Translation: ABC86949.1.
DQ356646 Genomic DNA. Translation: ABC86950.1.
Z49705 Genomic DNA. Translation: CAA89803.1.
BK006946 Genomic DNA. Translation: DAA10063.1.
PIRS54525.
RefSeqNP_013890.1. NM_001182671.1.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4E4WX-ray2.50A485-769[»]
4FMNX-ray2.69A485-769[»]
4FMOX-ray3.04A485-769[»]
ProteinModelPortalP38920.
SMRP38920. Positions 5-298, 509-769.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid35345. 95 interactions.
DIPDIP-2412N.
IntActP38920. 7 interactions.
MINTMINT-625234.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblFungiYMR167W; YMR167W; YMR167W.
GeneID855203.
KEGGsce:YMR167W.

Organism-specific databases

CYGDYMR167w.
SGDS000004777. MLH1.

Phylogenomic databases

GeneTreeENSGT00550000074923.
KOK08734.
OMAINHRCVE.
OrthoDBEOG72RN8H.

Enzyme and pathway databases

BioCycYEAST:G3O-32857-MONOMER.

Gene expression databases

GenevestigatorP38920.

Family and domain databases

Gene3D3.30.230.10. 1 hit.
3.30.565.10. 1 hit.
InterProIPR013507. DNA_mismatch_repair_C.
IPR014762. DNA_mismatch_repair_CS.
IPR002099. DNA_mismatch_repair_fam.
IPR011186. DNA_mismatch_repair_MLH1.
IPR003594. HATPase_ATP-bd.
IPR020568. Ribosomal_S5_D2-typ_fold.
IPR014721. Ribosomal_S5_D2-typ_fold_subgr.
[Graphical view]
PANTHERPTHR10073. PTHR10073. 1 hit.
PTHR10073:SF11. PTHR10073:SF11. 1 hit.
PfamPF01119. DNA_mis_repair. 1 hit.
[Graphical view]
SMARTSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMSSF54211. SSF54211. 1 hit.
SSF55874. SSF55874. 1 hit.
TIGRFAMsTIGR00585. mutl. 1 hit.
PROSITEPS00058. DNA_MISMATCH_REPAIR_1. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio978693.
PROP38920.

Entry information

Entry nameMLH1_YEAST
AccessionPrimary (citable) accession number: P38920
Secondary accession number(s): D6VZY9 expand/collapse secondary AC list , Q2I028, Q2I029, Q2I031, Q2I032, Q2I033, Q2I034, Q2I035, Q2I036, Q2I038, Q2I039, Q2I041
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: October 1, 1996
Last modified: April 16, 2014
This is version 135 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programFungal Protein Annotation Program

Relevant documents

Yeast chromosome XIII

Yeast (Saccharomyces cerevisiae) chromosome XIII: entries and gene names

Yeast

Yeast (Saccharomyces cerevisiae): entries, gene names and cross-references to SGD

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references