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Protein

DNA mismatch repair protein MLH1

Gene

MLH1

Organism
Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.3 Publications

Kineticsi

  1. KM=69 µM for ATP1 Publication

    GO - Molecular functioni

    • ATPase activity Source: SGD
    • ATP binding Source: SGD
    • mismatched DNA binding Source: InterPro

    GO - Biological processi

    • meiotic heteroduplex formation Source: SGD
    • meiotic mismatch repair Source: SGD
    • mismatch repair Source: SGD
    • reciprocal meiotic recombination Source: SGD
    Complete GO annotation...

    Keywords - Biological processi

    DNA damage, DNA repair

    Enzyme and pathway databases

    BioCyciYEAST:G3O-32857-MONOMER.
    ReactomeiR-SCE-5358565. Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    DNA mismatch repair protein MLH1
    Alternative name(s):
    MutL protein homolog 1
    Post meiotic segregation protein 2
    Gene namesi
    Name:MLH1
    Synonyms:PMS2
    Ordered Locus Names:YMR167W
    ORF Names:YM8520.16
    OrganismiSaccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
    Taxonomic identifieri559292 [NCBI]
    Taxonomic lineageiEukaryotaFungiDikaryaAscomycotaSaccharomycotinaSaccharomycetesSaccharomycetalesSaccharomycetaceaeSaccharomyces
    Proteomesi
    • UP000002311 Componenti: Chromosome XIII

    Organism-specific databases

    EuPathDBiFungiDB:YMR167W.
    SGDiS000004777. MLH1.

    Subcellular locationi

    GO - Cellular componenti

    • chiasma Source: GO_Central
    • MutLalpha complex Source: SGD
    • MutLgamma complex Source: SGD
    • synaptonemal complex Source: GO_Central
    Complete GO annotation...

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi31E → A: Reduces ATPase activity by 98%. Displays 3300-fold increase in spontaneous mutation accumulation. 2 Publications1
    Mutagenesisi35N → A: Abolishes ATP binding, reducing ATPase activity by 95%. Displays 9800-fold increase in spontaneous mutation accumulation. 1 Publication1
    Mutagenesisi41A → F: Defective in a mismatch repair assay. Abolishes heterodimer formation. Displays an increases spontaneous mutation accumulation. 2 Publications1
    Mutagenesisi41A → G: Reduces heterodimer formation. Displays an weak increase in spontaneous mutation accumulation. 2 Publications1
    Mutagenesisi41A → S: Fully functional in a mismatch repair assay. 2 Publications1
    Mutagenesisi64G → R: Defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi65I → N: Defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi96F → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. 1 Publication1
    Mutagenesisi97R → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. 1 Publication1
    Mutagenesisi98G → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. 2 Publications1
    Mutagenesisi98G → V: Abolishes heterodimer formation. Displays an increase in spontaneous mutation accumulation. 2 Publications1
    Mutagenesisi99E → K: Defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi104I → R: Defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi114T → R: Defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi214R → C: Partially defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi216V → I: Fully functional in a mismatch repair assay. 1 Publication1
    Mutagenesisi265R → C: Partially defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi265R → H: Partially defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi273R → E: Strongly reduces DNA-binding and displays 12000-fold increase in spontaneous mutation accumulation; when associated with E-274. 1 Publication1
    Mutagenesisi274R → 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. 1 Publication1
    Mutagenesisi326I → A: Partially defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi326I → V: Fully functional in a mismatch repair assay. 1 Publication1
    Mutagenesisi552Q → L: Defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi672R → P: Defective in a mismatch repair assay. 1 Publication1
    Mutagenesisi694A → T: Fully functional in a mismatch repair assay. 1 Publication1
    Mutagenesisi764K → E: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. 1 Publication1
    Mutagenesisi764K → R: No effect. 1 Publication1
    Mutagenesisi766F → A: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. 1 Publication1
    Mutagenesisi767E → D: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. 1 Publication1
    Mutagenesisi769C → A: No effect. 1 Publication1
    Mutagenesisi769C → S: Displays an increase in spontaneous mutation accumulation. Does not impair heterodimer formation. 1 Publication1

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001780081 – 769DNA mismatch repair protein MLH1Add BLAST769

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei441Phosphoserine; by ATM or ATRCombined sources1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiP38920.
    PRIDEiP38920.

    PTM databases

    iPTMnetiP38920.

    Interactioni

    Subunit structurei

    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 MLH2.1 Publication

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    MLH2Q079805EBI-11003,EBI-33369
    MLH3Q120834EBI-11003,EBI-31634
    PMS1P142427EBI-11003,EBI-13561

    Protein-protein interaction databases

    BioGridi35345. 97 interactors.
    DIPiDIP-2412N.
    IntActiP38920. 7 interactors.
    MINTiMINT-625234.

    Structurei

    Secondary structure

    1769
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi512 – 524Combined sources13
    Helixi527 – 534Combined sources8
    Beta strandi537 – 543Combined sources7
    Turni544 – 547Combined sources4
    Beta strandi548 – 553Combined sources6
    Beta strandi556 – 561Combined sources6
    Helixi562 – 577Combined sources16
    Beta strandi582 – 585Combined sources4
    Helixi591 – 593Combined sources3
    Helixi597 – 601Combined sources5
    Helixi610 – 622Combined sources13
    Helixi624 – 631Combined sources8
    Beta strandi634 – 639Combined sources6
    Helixi644 – 646Combined sources3
    Beta strandi647 – 654Combined sources8
    Helixi666 – 675Combined sources10
    Helixi682 – 697Combined sources16
    Helixi714 – 733Combined sources20
    Helixi735 – 742Combined sources8
    Helixi747 – 752Combined sources6
    Beta strandi753 – 758Combined sources6
    Helixi759 – 765Combined sources7

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    4E4WX-ray2.50A485-769[»]
    4FMNX-ray2.69A485-769[»]
    4FMOX-ray3.04A485-769[»]
    ProteinModelPortaliP38920.
    SMRiP38920.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni1 – 335DNA- and ATP-bindingAdd BLAST335
    Regioni501 – 756Interaction with PMS1Add BLAST256

    Sequence similaritiesi

    Phylogenomic databases

    GeneTreeiENSGT00800000124177.
    InParanoidiP38920.
    KOiK08734.
    OMAiINHRCVE.
    OrthoDBiEOG092C22BC.

    Family and domain databases

    Gene3Di3.30.230.10. 1 hit.
    3.30.565.10. 1 hit.
    InterProiIPR013507. DNA_mismatch_repair_C.
    IPR014762. DNA_mismatch_repair_CS.
    IPR002099. DNA_mismatch_repair_fam.
    IPR003594. HATPase_C.
    IPR032189. Mlh1_C.
    IPR020568. Ribosomal_S5_D2-typ_fold.
    IPR014721. Ribosomal_S5_D2-typ_fold_subgr.
    [Graphical view]
    PfamiPF01119. DNA_mis_repair. 1 hit.
    PF16413. Mlh1_C. 1 hit.
    [Graphical view]
    SMARTiSM01340. DNA_mis_repair. 1 hit.
    [Graphical view]
    SUPFAMiSSF54211. SSF54211. 1 hit.
    SSF55874. SSF55874. 1 hit.
    TIGRFAMsiTIGR00585. mutl. 1 hit.
    PROSITEiPS00058. DNA_MISMATCH_REPAIR_1. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P38920-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSLRIKALDA SVVNKIAAGE IIISPVNALK EMMENSIDAN ATMIDILVKE
    60 70 80 90 100
    GGIKVLQITD NGSGINKADL PILCERFTTS KLQKFEDLSQ IQTYGFRGEA
    110 120 130 140 150
    LASISHVARV TVTTKVKEDR CAWRVSYAEG KMLESPKPVA GKDGTTILVE
    160 170 180 190 200
    DLFFNIPSRL RALRSHNDEY SKILDVVGRY AIHSKDIGFS CKKFGDSNYS
    210 220 230 240 250
    LSVKPSYTVQ DRIRTVFNKS VASNLITFHI SKVEDLNLES VDGKVCNLNF
    260 270 280 290 300
    ISKKSISPIF FINNRLVTCD LLRRALNSVY SNYLPKGNRP FIYLGIVIDP
    310 320 330 340 350
    AAVDVNVHPT KREVRFLSQD EIIEKIANQL HAELSAIDTS RTFKASSIST
    360 370 380 390 400
    NKPESLIPFN DTIESDRNRK SLRQAQVVEN SYTTANSQLR KAKRQENKLV
    410 420 430 440 450
    RIDASQAKIT SFLSSSQQFN FEGSSTKRQL SEPKVTNVSH SQEAEKLTLN
    460 470 480 490 500
    ESEQPRDANT INDNDLKDQP KKKQKLGDYK VPSIADDEKN ALPISKDGYI
    510 520 530 540 550
    RVPKERVNVN LTSIKKLREK VDDSIHRELT DIFANLNYVG VVDEERRLAA
    560 570 580 590 600
    IQHDLKLFLI DYGSVCYELF YQIGLTDFAN FGKINLQSTN VSDDIVLYNL
    610 620 630 640 650
    LSEFDELNDD ASKEKIISKI WDMSSMLNEY YSIELVNDGL DNDLKSVKLK
    660 670 680 690 700
    SLPLLLKGYI PSLVKLPFFI YRLGKEVDWE DEQECLDGIL REIALLYIPD
    710 720 730 740 750
    MVPKVDTSDA SLSEDEKAQF INRKEHISSL LEHVLFPCIK RRFLAPRHIL
    760
    KDVVEIANLP DLYKVFERC
    Length:769
    Mass (Da):87,062
    Last modified:October 1, 1996 - v2
    Checksum:iB2DBB31DE3943171
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti258P → L in AAA16835 (PubMed:8264608).Curated1
    Sequence conflicti288N → F in AAA16835 (PubMed:8264608).Curated1
    Sequence conflicti708S → L in AAA16835 (PubMed:8264608).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural varianti240S → R in strain: SK1. 1 Publication1
    Natural varianti242D → E in strain: YJM326 and YJM339. 1 Publication1
    Natural varianti271L → P in strain: EAY1066, EAY1068, M2-8, M7-8, M5-7, SK1, YJM269, YJM280, YJM320, YJM326, YJM339 and YJM627. 1 Publication1
    Natural varianti309P → L in strain: M2-8. 1 Publication1
    Natural varianti321E → D in strain: EAY1066. 1 Publication1
    Natural varianti333E → K in strain: SK1. 1 Publication1
    Natural varianti375A → T in strain: YJM339. 1 Publication1
    Natural varianti452S → G in strain: EAY1068, M2-8, M7-8, M5-7, YJM269 and YJM627. 1 Publication1
    Natural varianti465D → N in strain: EAY1066 and YJM280. 1 Publication1
    Natural varianti470P → S in strain: YJM339. 1 Publication1
    Natural varianti607L → F in strain: EAY1068, M2-8, M7-8, M5-7 and YJM627. 1 Publication1
    Natural varianti678D → N in strain: SK1, YJM320 and YJM339. 1 Publication1
    Natural varianti703P → L in strain: SK1, YJM320 and YJM339. 1 Publication1
    Natural varianti761D → 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. 1 Publication1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    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.
    PIRiS54525.
    RefSeqiNP_013890.1. NM_001182671.1.

    Genome annotation databases

    EnsemblFungiiYMR167W; YMR167W; YMR167W.
    GeneIDi855203.
    KEGGisce:YMR167W.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    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.
    PIRiS54525.
    RefSeqiNP_013890.1. NM_001182671.1.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    4E4WX-ray2.50A485-769[»]
    4FMNX-ray2.69A485-769[»]
    4FMOX-ray3.04A485-769[»]
    ProteinModelPortaliP38920.
    SMRiP38920.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi35345. 97 interactors.
    DIPiDIP-2412N.
    IntActiP38920. 7 interactors.
    MINTiMINT-625234.

    PTM databases

    iPTMnetiP38920.

    Proteomic databases

    MaxQBiP38920.
    PRIDEiP38920.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblFungiiYMR167W; YMR167W; YMR167W.
    GeneIDi855203.
    KEGGisce:YMR167W.

    Organism-specific databases

    EuPathDBiFungiDB:YMR167W.
    SGDiS000004777. MLH1.

    Phylogenomic databases

    GeneTreeiENSGT00800000124177.
    InParanoidiP38920.
    KOiK08734.
    OMAiINHRCVE.
    OrthoDBiEOG092C22BC.

    Enzyme and pathway databases

    BioCyciYEAST:G3O-32857-MONOMER.
    ReactomeiR-SCE-5358565. Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).

    Miscellaneous databases

    PROiP38920.

    Family and domain databases

    Gene3Di3.30.230.10. 1 hit.
    3.30.565.10. 1 hit.
    InterProiIPR013507. DNA_mismatch_repair_C.
    IPR014762. DNA_mismatch_repair_CS.
    IPR002099. DNA_mismatch_repair_fam.
    IPR003594. HATPase_C.
    IPR032189. Mlh1_C.
    IPR020568. Ribosomal_S5_D2-typ_fold.
    IPR014721. Ribosomal_S5_D2-typ_fold_subgr.
    [Graphical view]
    PfamiPF01119. DNA_mis_repair. 1 hit.
    PF16413. Mlh1_C. 1 hit.
    [Graphical view]
    SMARTiSM01340. DNA_mis_repair. 1 hit.
    [Graphical view]
    SUPFAMiSSF54211. SSF54211. 1 hit.
    SSF55874. SSF55874. 1 hit.
    TIGRFAMsiTIGR00585. mutl. 1 hit.
    PROSITEiPS00058. DNA_MISMATCH_REPAIR_1. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiMLH1_YEAST
    AccessioniPrimary (citable) accession number: P38920
    Secondary accession number(s): D6VZY9
    , Q2I028, Q2I029, Q2I031, Q2I032, Q2I033, Q2I034, Q2I035, Q2I036, Q2I038, Q2I039, Q2I041
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1995
    Last sequence update: October 1, 1996
    Last modified: November 2, 2016
    This is version 161 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programFungal Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    Present with 319 molecules/cell in log phase SD medium.1 Publication

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families
    3. Yeast
      Yeast (Saccharomyces cerevisiae): entries, gene names and cross-references to SGD
    4. Yeast chromosome XIII
      Yeast (Saccharomyces cerevisiae) chromosome XIII: entries and gene names

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.