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P40692

- MLH1_HUMAN

UniProt

P40692 - MLH1_HUMAN

Protein

DNA mismatch repair protein Mlh1

Gene

MLH1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 171 (01 Oct 2014)
      Sequence version 1 (01 Feb 1995)
      Previous versions | rss
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    Functioni

    Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.2 Publications

    GO - Molecular functioni

    1. ATPase activity Source: RefGenome
    2. ATP binding Source: InterPro
    3. guanine/thymine mispair binding Source: Ensembl
    4. protein binding Source: UniProtKB

    GO - Biological processi

    1. ATP catabolic process Source: GOC
    2. double-strand break repair via nonhomologous end joining Source: Ensembl
    3. intrinsic apoptotic signaling pathway in response to DNA damage Source: Ensembl
    4. isotype switching Source: Ensembl
    5. male meiosis chromosome segregation Source: Ensembl
    6. meiotic metaphase I plate congression Source: Ensembl
    7. mismatch repair Source: MGI
    8. negative regulation of mitotic recombination Source: Ensembl
    9. nuclear-transcribed mRNA poly(A) tail shortening Source: Ensembl
    10. oogenesis Source: Ensembl
    11. resolution of meiotic recombination intermediates Source: Ensembl
    12. somatic hypermutation of immunoglobulin genes Source: RefGenome
    13. spermatogenesis Source: Ensembl
    14. spindle midzone assembly involved in meiosis Source: Ensembl
    15. synapsis Source: Ensembl

    Keywords - Biological processi

    Cell cycle, DNA damage, DNA repair

    Enzyme and pathway databases

    ReactomeiREACT_27271. Meiotic recombination.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    DNA mismatch repair protein Mlh1
    Alternative name(s):
    MutL protein homolog 1
    Gene namesi
    Name:MLH1
    Synonyms:COCA2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 3

    Organism-specific databases

    HGNCiHGNC:7127. MLH1.

    Subcellular locationi

    Nucleus 2 Publications

    GO - Cellular componenti

    1. chiasma Source: RefGenome
    2. male germ cell nucleus Source: Ensembl
    3. membrane Source: UniProtKB
    4. MutLalpha complex Source: RefGenome
    5. nucleus Source: HGNC
    6. synaptonemal complex Source: RefGenome

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Hereditary non-polyposis colorectal cancer 2 (HNPCC2) [MIM:609310]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected.55 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti18 – 181R → C in HNPCC2. 1 Publication
    VAR_022663
    Natural varianti19 – 191I → F in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043383
    Natural varianti21 – 211A → V in HNPCC2. 1 Publication
    VAR_043384
    Natural varianti25 – 251I → F in HNPCC2. 1 Publication
    VAR_043385
    Natural varianti28 – 281P → L in HNPCC2. 5 Publications
    VAR_004433
    Natural varianti29 – 291A → S in HNPCC2; unknown pathological significance; has no effect on ex vivo splicing assay. 2 Publications
    VAR_043386
    Natural varianti35 – 351M → K in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043387
    Natural varianti35 – 351M → R in HNPCC2.
    VAR_004434
    Natural varianti38 – 381N → H in HNPCC2. 1 Publication
    VAR_043389
    Natural varianti41 – 411D → G in HNPCC2. 1 Publication
    VAR_043390
    Natural varianti41 – 411D → H Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054522
    Natural varianti44 – 441S → F in HNPCC2; the equivalent substitution in yeast causes loss of function in a mismatch repair assay; has no effect on ex vivo splicing assay. 1 Publication
    VAR_004436
    Natural varianti45 – 473TSI → CF in HNPCC2.
    VAR_043391
    Natural varianti62 – 621Q → K in HNPCC2; reduced repair efficiency in a yeast mismatch repair assay. 1 Publication
    VAR_004437
    Natural varianti63 – 631D → E in HNPCC2. 1 Publication
    VAR_043392
    Natural varianti64 – 641N → S in HNPCC2. 1 Publication
    VAR_004438
    Natural varianti67 – 671G → R in HNPCC2; the equivalent substitution in yeast causes loss of function in a mismatch repair assay; has no effect on ex vivo splicing assay. 8 Publications
    VAR_004439
    Natural varianti67 – 671G → W in HNPCC2. 2 Publications
    VAR_012903
    Natural varianti68 – 681I → N in HNPCC2; the equivalent substitution in yeast causes loss of function in a mismatch repair assay. 1 Publication
    VAR_004440
    Natural varianti69 – 691R → K in HNPCC2; reduced repair efficiency in a mismatch repair assay. 1 Publication
    VAR_004441
    Natural varianti71 – 711Missing in HNPCC2. 1 Publication
    VAR_043393
    Natural varianti77 – 771C → R in HNPCC2 and CRC; sporadic; normal interaction with PMS2; loss of function in a mismatch repair assay. 3 Publications
    VAR_004442
    Natural varianti80 – 801F → V in HNPCC2. 2 Publications
    VAR_012905
    Natural varianti84 – 841K → E in HNPCC2. 2 Publications
    VAR_012906
    Natural varianti98 – 981G → S Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054523
    Natural varianti101 – 1011G → D in HNPCC2; has no effect on ex vivo splicing assay. 2 Publications
    VAR_022664
    Natural varianti101 – 1011G → S Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054524
    Natural varianti102 – 1021E → K in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043394
    Natural varianti107 – 1071I → R in HNPCC2; normal interaction with PMS2; loss of function in a mismatch repair assay. 1 Publication
    VAR_004444
    Natural varianti111 – 1111A → V in HNPCC2; unknown pathological significance. 2 Publications
    VAR_012907
    Natural varianti116 – 1161T → K Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054525
    Natural varianti117 – 1171T → M in HNPCC2; fails to interact with PMS2 and EXO1; loss of function in a mismatch repair assay; has no effect on ex vivo splicing assay. 7 Publications
    VAR_004445
    Natural varianti117 – 1171T → R in HNPCC2; equivalent substitution in yeast causes loss of function in mismatch repair assay. 1 Publication
    VAR_004446
    Natural varianti126 – 1261Y → N Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    Corresponds to variant rs200076893 [ dbSNP | Ensembl ].
    VAR_054526
    Natural varianti128 – 1281A → P in HNPCC2. 1 Publication
    VAR_012908
    Natural varianti155 – 1551L → R in HNPCC2. 1 Publication
    VAR_043397
    Natural varianti182 – 1821R → G in HNPCC2; incomplete. 2 Publications
    VAR_012909
    Natural varianti182 – 1821R → K in HNPCC2. 1 Publication
    VAR_022666
    Natural varianti185 – 1851V → G in HNPCC2; defective in a mismatch repair assay; has no effect on ex vivo splicing assay. 1 Publication
    VAR_004447
    Natural varianti185 – 1851V → L in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043398
    Natural varianti193 – 1931S → P in HNPCC2. 1 Publication
    VAR_004448
    Natural varianti213 – 2131V → M Associated with HNPCC2; has no effect on ex vivo splicing assay. 5 Publications
    Corresponds to variant rs2308317 [ dbSNP | Ensembl ].
    VAR_012910
    Natural varianti215 – 2151N → S Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054527
    Natural varianti216 – 2161I → S Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054528
    Natural varianti217 – 2171R → C in HNPCC2; unknown pathological significance; proficient in a mismatch repair assay. 3 Publications
    Corresponds to variant rs4986984 [ dbSNP | Ensembl ].
    VAR_004449
    Natural varianti226 – 29570Missing in HNPCC2.
    VAR_004452Add
    BLAST
    Natural varianti226 – 2261R → L in HNPCC2. 1 Publication
    VAR_004451
    Natural varianti234 – 2341E → G in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043399
    Natural varianti244 – 2441G → D in HNPCC2; defective in a mismatch repair assay. 2 Publications
    VAR_012911
    Natural varianti247 – 2471S → P in HNPCC2. 2 Publications
    VAR_043400
    Natural varianti260 – 2601L → F Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054529
    Natural varianti262 – 2621Missing in HNPCC2. 1 Publication
    VAR_012913
    Natural varianti264 – 2641H → Y in HNPCC2. 1 Publication
    VAR_043402
    Natural varianti265 – 2651R → C Associated with HNPCC2; results in partial exon 10 skipping on ex vivo splicing assay. 1 Publication
    VAR_054530
    Natural varianti265 – 2651R → H Rare polymorphism; associated with HNPCC2; slightly lower mismatch repair efficiency; results in partial exon 10 skipping on ex vivo splicing assay. 3 Publications
    VAR_012914
    Natural varianti282 – 2821A → G in HNPCC2. 1 Publication
    VAR_043403
    Natural varianti292 – 2921L → P in HNPCC2; unknown pathological significance. 2 Publications
    VAR_043404
    Natural varianti295 – 2951S → T in HNPCC2. 1 Publication
    VAR_012916
    Natural varianti304 – 3041D → V in HNPCC2. 1 Publication
    VAR_043405
    Natural varianti320 – 3201E → D Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054531
    Natural varianti321 – 3211S → I in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043406
    Natural varianti326 – 3261V → A in HNPCC2; proficient in a mismatch repair assay. 2 Publications
    Corresponds to variant rs63751049 [ dbSNP | Ensembl ].
    VAR_004453
    Natural varianti329 – 3291H → P in HNPCC2. 4 Publications
    VAR_012918
    Natural varianti330 – 3301Missing in HNPCC2; results in weak exon 11 skipping on ex vivo splicing assay. 2 Publications
    VAR_043408
    Natural varianti338 – 3381N → S in HNPCC2. 1 Publication
    VAR_043409
    Natural varianti379 – 3791Y → C in HNPCC2. 1 Publication
    VAR_022667
    Natural varianti385 – 3851R → C in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043410
    Natural varianti385 – 3851R → P in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043411
    Natural varianti441 – 4411A → T in HNPCC2. 2 Publications
    VAR_012920
    Natural varianti474 – 4741R → Q in HNPCC2; unknown pathological significance. 2 Publications
    VAR_043414
    Natural varianti474 – 4741R → W Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054532
    Natural varianti485 – 4851D → E in HNPCC2. 1 Publication
    VAR_043415
    Natural varianti485 – 4851D → H in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043416
    Natural varianti492 – 4921A → T in HNPCC2 and CRC; sporadic. 1 Publication
    VAR_004455
    Natural varianti506 – 5061V → A in HNPCC2.
    VAR_004456
    Natural varianti539 – 5391A → D Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054533
    Natural varianti542 – 5421Q → L in HNPCC2; type II; equivalent substitution in yeast causes loss of function in a mismatch repair assay. 3 Publications
    VAR_004457
    Natural varianti542 – 5421Q → P in HNPCC2. 1 Publication
    VAR_043417
    Natural varianti549 – 5491L → P in HNPCC2; has no effect on ex vivo splicing assay. 3 Publications
    VAR_012921
    Natural varianti550 – 5501L → P in HNPCC2. 1 Publication
    VAR_043418
    Natural varianti551 – 5511N → T in HNPCC2; has no effect on ex vivo splicing assay. 3 Publications
    VAR_012922
    Natural varianti559 – 5591L → R in HNPCC2. 1 Publication
    VAR_022668
    Natural varianti565 – 5651I → F in HNPCC2. 1 Publication
    VAR_012923
    Natural varianti574 – 5741L → P in HNPCC2; type I; abrogates interaction with EXO1. 3 Publications
    VAR_004458
    Natural varianti578 – 5781E → G in HNPCC2 and CRC. 1 Publication
    VAR_004459
    Natural varianti582 – 5821L → V in HNPCC2; type II. 1 Publication
    Corresponds to variant rs63751713 [ dbSNP | Ensembl ].
    VAR_004460
    Natural varianti585 – 5851L → R Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054534
    Natural varianti586 – 5861A → P in HNPCC2. 1 Publication
    VAR_015689
    Natural varianti588 – 5881L → P in HNPCC2. 1 Publication
    VAR_012924
    Natural varianti589 – 5891A → D in HNPCC2. 1 Publication
    VAR_043419
    Natural varianti596 – 5961Missing in HNPCC2.
    VAR_043420
    Natural varianti603 – 6031P → R in HNPCC2; unknown pathological significance; has no effect on ex vivo splicing assay. 3 Publications
    Corresponds to variant rs35831931 [ dbSNP | Ensembl ].
    VAR_012925
    Natural varianti607 – 6071L → H in LCIS and HNPCC2; unknown pathological significance; has no effect on ex vivo splicing assay; could determine an increased risk of colon cancer. 5 Publications
    Corresponds to variant rs41295284 [ dbSNP | Ensembl ].
    VAR_012926
    Natural varianti612 – 6121Missing in HNPCC2. 1 Publication
    VAR_043422
    Natural varianti616 – 6161Missing in HNPCC2 and MMRCS; abrogates interaction with EXO1; has no effect on ex vivo splicing assay. 9 Publications
    VAR_004461
    Natural varianti618 – 6181K → T in HNPCC2; type II. 5 Publications
    VAR_004463
    Natural varianti618 – 6181Missing in HNPCC2. 1 Publication
    VAR_043423
    Natural varianti619 – 6191A → P Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054535
    Natural varianti622 – 6221L → H in HNPCC2. 1 Publication
    VAR_012927
    Natural varianti623 – 6231A → P in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043425
    Natural varianti626 – 6272FS → ST in HNPCC2.
    VAR_004464
    Natural varianti631 – 6311D → A in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043426
    Natural varianti636 – 6361L → P in HNPCC2. 1 Publication
    VAR_043428
    Natural varianti640 – 6401P → L Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054536
    Natural varianti640 – 6401P → S in HNPCC2; has no effect on ex vivo splicing assay. 2 Publications
    VAR_043429
    Natural varianti646 – 6461Y → C in HNPCC2; unknown pathological significance. 2 Publications
    Corresponds to variant rs35045067 [ dbSNP | Ensembl ].
    VAR_043430
    Natural varianti648 – 6481P → L in HNPCC2. 2 Publications
    VAR_012928
    Natural varianti648 – 6481P → S in HNPCC2; protein unstable but still functional in mismatch repair. 3 Publications
    VAR_022669
    Natural varianti654 – 6541P → L in HNPCC2. 1 Publication
    VAR_043431
    Natural varianti655 – 6551I → V Found in an endometrial cancer sample; also associated with HNPCC2; has no effect on ex vivo splicing assay. 2 Publications
    Corresponds to variant rs55907433 [ dbSNP | Ensembl ].
    VAR_043432
    Natural varianti656 – 6561F → S Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054537
    Natural varianti657 – 6571Missing in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043433
    Natural varianti659 – 6591R → L in HNPCC2. 1 Publication
    VAR_012929
    Natural varianti659 – 6591R → P in HNPCC2; interacts only very weakly with PMS2; equivalent substitution in yeast causes almost complete loss of function in a mismatch repair assay; abrogates interaction with EXO1. 2 Publications
    VAR_004465
    Natural varianti662 – 6621T → P in HNPCC2; unknown pathological significance. 2 Publications
    VAR_012930
    Natural varianti666 – 6661W → R Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054538
    Natural varianti681 – 6811A → T in HNPCC2; unknown pathological significance; equivalent substitution in yeast does not affect mismatch repair; abrogates interaction with EXO1. 5 Publications
    VAR_004466
    Natural varianti687 – 6871R → W in HNPCC2; unknown pathological significance. 3 Publications
    VAR_012931
    Natural varianti718 – 7181H → Y in HNPCC2; unknown pathological significance. 3 Publications
    Corresponds to variant rs2020873 [ dbSNP | Ensembl ].
    VAR_004467
    Natural varianti719 – 7191I → INVFHI in HNPCC2.
    VAR_043435
    Natural varianti724 – 7241L → M in HNPCC2. 1 Publication
    VAR_043436
    Natural varianti751 – 7511K → R in HNPCC2; unknown pathological significance. 3 Publications
    VAR_012934
    Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. Areas of skin hypopigmentation have also been reported in MMRCS patients.2 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti35 – 351M → N in MMRCS; requires 2 nucleotide substitutions. 2 Publications
    VAR_043388
    Natural varianti616 – 6161Missing in HNPCC2 and MMRCS; abrogates interaction with EXO1; has no effect on ex vivo splicing assay. 9 Publications
    VAR_004461
    Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.
    Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids.
    Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
    Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.

    Keywords - Diseasei

    Disease mutation, Hereditary nonpolyposis colorectal cancer, Tumor suppressor

    Organism-specific databases

    MIMi158320. phenotype.
    276300. phenotype.
    608089. phenotype.
    609310. phenotype.
    Orphaneti252202. Constitutional mismatch repair deficiency syndrome.
    144. Hereditary nonpolyposis colon cancer.
    587. Muir-Torre syndrome.
    99817. Non-polyposis Turcot syndrome.
    PharmGKBiPA240.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed1 Publication
    Chaini2 – 756755DNA mismatch repair protein Mlh1PRO_0000178000Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserine1 Publication
    Modified residuei477 – 4771Phosphoserine3 Publications

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP40692.
    PaxDbiP40692.
    PRIDEiP40692.

    PTM databases

    PhosphoSiteiP40692.

    Miscellaneous databases

    PMAP-CutDBP40692.

    Expressioni

    Tissue specificityi

    Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart.

    Gene expression databases

    ArrayExpressiP40692.
    BgeeiP40692.
    CleanExiHS_MLH1.
    GenevestigatoriP40692.

    Organism-specific databases

    HPAiCAB013294.
    HPA052707.

    Interactioni

    Subunit structurei

    Heterodimer of MLH1 and PMS2 (MutL alpha), MLH1 and PMS1 (MutL beta) or MLH1 and MLH3 (MutL gamma). Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with MBD4. Interacts with EXO1 and MTMR15/FAN1.6 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ACTG1P632617EBI-744248,EBI-351292
    ANXA2P073557EBI-744248,EBI-352622
    BRIP1Q9BX6311EBI-744248,EBI-3509650
    CTSBP078587EBI-744248,EBI-715062
    DESP176617EBI-744248,EBI-1055572
    FSCN1Q166587EBI-744248,EBI-351076
    NT5C3BQ969T73EBI-744248,EBI-2932564
    PMS2P542784EBI-744248,EBI-1162561
    SPTAN1Q138137EBI-744248,EBI-351450
    TMSB4XP6232816EBI-744248,EBI-712598
    ZC3H11AO751523EBI-744248,EBI-748480

    Protein-protein interaction databases

    BioGridi110438. 117 interactions.
    DIPiDIP-27601N.
    IntActiP40692. 97 interactions.
    MINTiMINT-257265.
    STRINGi9606.ENSP00000231790.

    Structurei

    Secondary structure

    1
    756
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi13 – 2513
    Helixi28 – 4114
    Beta strandi45 – 528
    Turni53 – 564
    Beta strandi57 – 637
    Helixi70 – 723
    Turni73 – 775
    Helixi103 – 1097
    Beta strandi110 – 1189
    Beta strandi122 – 13110
    Beta strandi134 – 1374
    Beta strandi140 – 1423
    Beta strandi146 – 1549
    Turni155 – 1584
    Helixi160 – 1656
    Helixi169 – 18618
    Turni187 – 1893
    Beta strandi190 – 1967
    Beta strandi203 – 2053
    Helixi212 – 2209
    Helixi222 – 2254
    Beta strandi228 – 2358
    Turni236 – 2394
    Beta strandi240 – 2478
    Beta strandi253 – 2553
    Beta strandi257 – 2626
    Helixi270 – 28112
    Beta strandi291 – 2988
    Helixi322 – 33514
    Helixi504 – 51613
    Helixi519 – 5268
    Beta strandi529 – 54315
    Beta strandi546 – 5516
    Helixi552 – 56615
    Beta strandi572 – 58110
    Helixi582 – 5909
    Helixi593 – 5953
    Helixi604 – 62623
    Beta strandi634 – 6418
    Helixi650 – 6523
    Helixi653 – 66210
    Helixi669 – 68416
    Helixi688 – 6903
    Helixi712 – 7187
    Helixi720 – 7245
    Helixi732 – 7354
    Beta strandi737 – 7459

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    3NA3X-ray2.50A1-347[»]
    3RBNX-ray2.16A/B486-751[»]
    4P7AX-ray2.30A1-347[»]
    ProteinModelPortaliP40692.
    SMRiP40692. Positions 3-335, 487-751.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP40692.

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni410 – 650241Interaction with EXO1Add
    BLAST

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiCOG0323.
    HOGENOMiHOG000176000.
    HOVERGENiHBG006374.
    InParanoidiP40692.
    KOiK08734.
    OMAiINHRCVE.
    OrthoDBiEOG7MSMNH.
    PhylomeDBiP40692.
    TreeFamiTF300493.

    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.
    IPR011186. DNA_mismatch_repair_MLH1/HexB.
    IPR003594. HATPase_ATP-bd.
    IPR020568. Ribosomal_S5_D2-typ_fold.
    IPR014721. Ribosomal_S5_D2-typ_fold_subgr.
    [Graphical view]
    PANTHERiPTHR10073:SF12. PTHR10073:SF12. 1 hit.
    PfamiPF01119. DNA_mis_repair. 1 hit.
    [Graphical view]
    SMARTiSM00387. HATPase_c. 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]

    Sequences (3)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P40692-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MSFVAGVIRR LDETVVNRIA AGEVIQRPAN AIKEMIENCL DAKSTSIQVI    50
    VKEGGLKLIQ IQDNGTGIRK EDLDIVCERF TTSKLQSFED LASISTYGFR 100
    GEALASISHV AHVTITTKTA DGKCAYRASY SDGKLKAPPK PCAGNQGTQI 150
    TVEDLFYNIA TRRKALKNPS EEYGKILEVV GRYSVHNAGI SFSVKKQGET 200
    VADVRTLPNA STVDNIRSIF GNAVSRELIE IGCEDKTLAF KMNGYISNAN 250
    YSVKKCIFLL FINHRLVEST SLRKAIETVY AAYLPKNTHP FLYLSLEISP 300
    QNVDVNVHPT KHEVHFLHEE SILERVQQHI ESKLLGSNSS RMYFTQTLLP 350
    GLAGPSGEMV KSTTSLTSSS TSGSSDKVYA HQMVRTDSRE QKLDAFLQPL 400
    SKPLSSQPQA IVTEDKTDIS SGRARQQDEE MLELPAPAEV AAKNQSLEGD 450
    TTKGTSEMSE KRGPTSSNPR KRHREDSDVE MVEDDSRKEM TAACTPRRRI 500
    INLTSVLSLQ EEINEQGHEV LREMLHNHSF VGCVNPQWAL AQHQTKLYLL 550
    NTTKLSEELF YQILIYDFAN FGVLRLSEPA PLFDLAMLAL DSPESGWTEE 600
    DGPKEGLAEY IVEFLKKKAE MLADYFSLEI DEEGNLIGLP LLIDNYVPPL 650
    EGLPIFILRL ATEVNWDEEK ECFESLSKEC AMFYSIRKQY ISEESTLSGQ 700
    QSEVPGSIPN SWKWTVEHIV YKALRSHILP PKHFTEDGNI LQLANLPDLY 750
    KVFERC 756
    Length:756
    Mass (Da):84,601
    Last modified:February 1, 1995 - v1
    Checksum:iC9231FC406C2CA20
    GO
    Isoform 2 (identifier: P40692-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-241: Missing.

    Show »
    Length:515
    Mass (Da):58,375
    Checksum:iDCD9320AB8E5ADF5
    GO
    Isoform 3 (identifier: P40692-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-101: MSFVAGVIRR...ASISTYGFRG → MAF

    Note: No experimental confirmation available.

    Show »
    Length:658
    Mass (Da):73,837
    Checksum:iC7ED5BB8A39DA389
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti352 – 3521L → H in BAG60773. (PubMed:14702039)Curated
    Sequence conflicti708 – 7114Missing in AAA85687. (PubMed:7757073)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti18 – 181R → C in HNPCC2. 1 Publication
    VAR_022663
    Natural varianti19 – 191I → F in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043383
    Natural varianti21 – 211A → V in HNPCC2. 1 Publication
    VAR_043384
    Natural varianti22 – 221G → A.1 Publication
    Corresponds to variant rs41295280 [ dbSNP | Ensembl ].
    VAR_038023
    Natural varianti25 – 251I → F in HNPCC2. 1 Publication
    VAR_043385
    Natural varianti28 – 281P → L in HNPCC2. 5 Publications
    VAR_004433
    Natural varianti29 – 291A → S in HNPCC2; unknown pathological significance; has no effect on ex vivo splicing assay. 2 Publications
    VAR_043386
    Natural varianti32 – 321I → V.1 Publication
    Corresponds to variant rs2020872 [ dbSNP | Ensembl ].
    VAR_014876
    Natural varianti35 – 351M → K in HNPCC2; unknown pathological significance. 1 Publication
    VAR_043387
    Natural varianti35 – 351M → N in MMRCS; requires 2 nucleotide substitutions. 2 Publications
    VAR_043388
    Natural varianti35 – 351M → R in HNPCC2.
    VAR_004434
    Natural varianti37 – 371E → ELNH Found in an endometrial cancer sample; somatic mutation.
    VAR_004435
    Natural varianti38 – 381N → H in HNPCC2. 1 Publication
    VAR_043389
    Natural varianti41 – 411D → G in HNPCC2. 1 Publication
    VAR_043390
    Natural varianti41 – 411D → H Associated with HNPCC2; has no effect on ex vivo splicing assay. 1 Publication
    VAR_054522
    Natural varianti44 – 441S → F in HNPCC2; the equivalent substitution in yeast causes loss of function in a mismatch repair assay; has no effect on ex vivo splicing assay. 1 Publication
    VAR_004436
    Natural varianti45 – 473TSI → CF in HNPCC2.
    VAR_043391
    Natural varianti54 – 541G → E in CRC; sporadic; somatic mutation. 1 Publication