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Protein

DNA mismatch repair protein Mlh1

Gene

Mlh1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

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 (By similarity).By similarity

GO - Molecular functioni

  • ATPase activity Source: GO_Central
  • ATP binding Source: InterPro
  • guanine/thymine mispair binding Source: MGI
  • single-stranded DNA binding Source: GO_Central
  • structure-specific DNA binding Source: MGI

GO - Biological processi

  • cellular response to DNA damage stimulus Source: MGI
  • DNA repair Source: MGI
  • double-strand break repair via nonhomologous end joining Source: MGI
  • female meiosis chromosome segregation Source: MGI
  • homologous chromosome segregation Source: MGI
  • intrinsic apoptotic signaling pathway in response to DNA damage Source: MGI
  • isotype switching Source: MGI
  • male meiosis Source: MGI
  • male meiosis chromosome segregation Source: MGI
  • meiotic chromosome segregation Source: MGI
  • meiotic metaphase I plate congression Source: MGI
  • meiotic nuclear division Source: MGI
  • meiotic spindle midzone assembly Source: MGI
  • mismatch repair Source: MGI
  • negative regulation of mitotic recombination Source: MGI
  • nuclear-transcribed mRNA poly(A) tail shortening Source: MGI
  • oogenesis Source: MGI
  • reciprocal meiotic recombination Source: MGI
  • resolution of meiotic recombination intermediates Source: MGI
  • somatic hypermutation of immunoglobulin genes Source: MGI
  • somatic recombination of immunoglobulin gene segments Source: MGI
  • somatic recombination of immunoglobulin genes involved in immune response Source: MGI
  • spermatogenesis Source: MGI
  • synapsis Source: MGI
Complete GO annotation...

Keywords - Biological processi

Cell cycle, DNA damage, DNA repair

Enzyme and pathway databases

ReactomeiREACT_27235. Meiotic Recombination.
REACT_309945. Meiotic recombination.
REACT_320650. Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
REACT_331202. Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).

Names & Taxonomyi

Protein namesi
Recommended name:
DNA mismatch repair protein Mlh1
Alternative name(s):
MutL protein homolog 1
Gene namesi
Name:Mlh1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:101938. Mlh1.

Subcellular locationi

GO - Cellular componenti

  • chiasma Source: MGI
  • chromosome Source: MGI
  • condensed chromosome Source: MGI
  • condensed nuclear chromosome Source: MGI
  • male germ cell nucleus Source: MGI
  • membrane Source: MGI
  • MutLalpha complex Source: MGI
  • nucleoplasm Source: MGI
  • synaptonemal complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 760759DNA mismatch repair protein Mlh1PRO_0000178001Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei481 – 4811PhosphoserineBy similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ9JK91.
PaxDbiQ9JK91.
PRIDEiQ9JK91.

PTM databases

PhosphoSiteiQ9JK91.

Expressioni

Gene expression databases

BgeeiQ9JK91.
CleanExiMM_MLH1.
ExpressionAtlasiQ9JK91. baseline and differential.
GenevisibleiQ9JK91. MM.

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 (By similarity).By similarity

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000035079.

Structurei

3D structure databases

ProteinModelPortaliQ9JK91.
SMRiQ9JK91. Positions 3-336, 492-755.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni412 – 654243Interaction with EXO1By similarityAdd
BLAST

Sequence similaritiesi

Phylogenomic databases

eggNOGiCOG0323.
GeneTreeiENSGT00790000123052.
HOGENOMiHOG000176000.
HOVERGENiHBG006374.
InParanoidiQ9JK91.
KOiK08734.
OMAiMVRTDCR.
OrthoDBiEOG7MSMNH.
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_C.
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]

Sequencei

Sequence statusi: Complete.

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

Q9JK91-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAFVAGVIRR LDETVVNRIA AGEVIQRPAN AIKEMIENCL DAKSTNIQVV
60 70 80 90 100
VKEGGLKLIQ IQDNGTGIRK EDLDIVCERF TTSKLQTFED LASISTYGFR
110 120 130 140 150
GEALASISHV AHVTITTKTA DGKCAYRASY SDGKLQAPPK PCAGNQGTLI
160 170 180 190 200
TVEDLFYNII TRRKALKNPS EEYGKILEVV GRYSIHNSGI SFSVKKQGET
210 220 230 240 250
VSDVRTLPNA TTVDNIRSIF GNAVSRELIE VGCEDKTLAF KMNGYISNAN
260 270 280 290 300
YSVKKCIFLL FINHRLVESA ALRKAIETVY AAYLPKNTHP FLYLSLEISP
310 320 330 340 350
QNVDVNVHPT KHEVHFLHEE SILQRVQQHI ESKLLGSNSS RMYFTQTLLP
360 370 380 390 400
GLAGPSGEAA RPTTGVASSS TSGSGDKVYA YQMVRTDSRE QKLDAFLQPV
410 420 430 440 450
SSLGPSQPQD PAPVRGARTE GSPERATRED EEMLALPAPA EAAAESENLE
460 470 480 490 500
RESLMETSDA AQKAAPTSSP GSSRKRHRED SDVEMVENAS GKEMTAACYP
510 520 530 540 550
RRRIINLTSV LSLQEEISER CHETLREMLR NHSFVGCVNP QWALAQHQTK
560 570 580 590 600
LYLLNTTKLS EELFYQILIY DFANFGVLRL SEPAPLFDLA MLALDSPESG
610 620 630 640 650
WTEDDGPKEG LAEYIVEFLK KKAEMLADYF SVEIDEEGNL IGLPLLIDSY
660 670 680 690 700
VPPLEGLPIF ILRLATEVNW DEEKECFESL SKECAMFYSI RKQYILEEST
710 720 730 740 750
LSGQQSDMPG STSKPWKWTV EHIIYKAFRS HLLPPKHFTE DGNVLQLANL
760
PDLYKVFERC
Length:760
Mass (Da):84,670
Last modified:July 27, 2011 - v2
Checksum:iB789D812F497FDF7
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti390 – 3901E → D in AAF64514 (Ref. 1) Curated
Sequence conflicti404 – 4041G → V in AAF64514 (Ref. 1) Curated
Sequence conflicti528 – 5281M → I in AAF64514 (Ref. 1) Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF250844 mRNA. Translation: AAF64514.1.
AK168849 mRNA. Translation: BAE40671.1.
U60872
, U59881, U59882, U59883, U59884 Genomic DNA. Translation: AAC52672.1.
CCDSiCCDS40784.1.
RefSeqiNP_081086.2. NM_026810.2.
UniGeneiMm.486383.

Genome annotation databases

EnsembliENSMUST00000035079; ENSMUSP00000035079; ENSMUSG00000032498.
GeneIDi17350.
KEGGimmu:17350.
UCSCiuc009rvp.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF250844 mRNA. Translation: AAF64514.1.
AK168849 mRNA. Translation: BAE40671.1.
U60872
, U59881, U59882, U59883, U59884 Genomic DNA. Translation: AAC52672.1.
CCDSiCCDS40784.1.
RefSeqiNP_081086.2. NM_026810.2.
UniGeneiMm.486383.

3D structure databases

ProteinModelPortaliQ9JK91.
SMRiQ9JK91. Positions 3-336, 492-755.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000035079.

PTM databases

PhosphoSiteiQ9JK91.

Proteomic databases

MaxQBiQ9JK91.
PaxDbiQ9JK91.
PRIDEiQ9JK91.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000035079; ENSMUSP00000035079; ENSMUSG00000032498.
GeneIDi17350.
KEGGimmu:17350.
UCSCiuc009rvp.2. mouse.

Organism-specific databases

CTDi4292.
MGIiMGI:101938. Mlh1.

Phylogenomic databases

eggNOGiCOG0323.
GeneTreeiENSGT00790000123052.
HOGENOMiHOG000176000.
HOVERGENiHBG006374.
InParanoidiQ9JK91.
KOiK08734.
OMAiMVRTDCR.
OrthoDBiEOG7MSMNH.
TreeFamiTF300493.

Enzyme and pathway databases

ReactomeiREACT_27235. Meiotic Recombination.
REACT_309945. Meiotic recombination.
REACT_320650. Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
REACT_331202. Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).

Miscellaneous databases

NextBioi291948.
PROiQ9JK91.
SOURCEiSearch...

Gene expression databases

BgeeiQ9JK91.
CleanExiMM_MLH1.
ExpressionAtlasiQ9JK91. baseline and differential.
GenevisibleiQ9JK91. MM.

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_C.
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]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Cloning of the cDNA of the MutL homolog, MLH1 from mouse testis."
    Kumaran M., Rao M.R.S.
    Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Testis.
  2. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Heart.
  3. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-151.

Entry informationi

Entry nameiMLH1_MOUSE
AccessioniPrimary (citable) accession number: Q9JK91
Secondary accession number(s): Q3TG77, Q62454
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: July 27, 2011
Last modified: June 24, 2015
This is version 122 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.