Reviewed, UniProtKB/Swiss-Prot Q9JK91 (MLH1_MOUSE)

Names and origin

Protein names

Recommended name:
    DNA mismatch repair protein Mlh1
Alternative name(s):
    MutL protein homolog 1

Gene names

Name:

Mlh1

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	760 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at transcript level.

General annotation (Comments)

Function	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.
Subunit structure	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 By similarity.
Subcellular location	Nucleus By similarity.
Sequence similarities	Belongs to the DNA mismatch repair mutL/hexB family.

Ontologies

Keywords
Biological process	Cell cycle DNA damage DNA repair
Cellular component	Nucleus
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	DNA damage response, signal transduction resulting in induction of apoptosis Inferred from mutant phenotype. Source: MGI double-strand break repair via nonhomologous end joining Inferred from mutant phenotype. Source: MGI isotype switching Inferred from mutant phenotype. Source: MGI male meiosis chromosome segregation Inferred from mutant phenotype. Source: MGI meiotic metaphase I plate congression Inferred from mutant phenotype. Source: MGI mismatch repair Ref.2 Inferred from direct assay. Source: MGI negative regulation of mitotic recombination Inferred from mutant phenotype. Source: MGI nuclear-transcribed mRNA poly(A) tail shortening Inferred from mutant phenotype. Source: MGI oogenesis Ref.2 Inferred from mutant phenotype. Source: MGI pachytene Ref.2 Inferred from mutant phenotype. Source: MGI resolution of meiotic joint molecules as recombinants Inferred from mutant phenotype. Source: MGI somatic hypermutation of immunoglobulin genes Inferred from mutant phenotype. Source: MGI spermatogenesis Ref.2 Inferred from mutant phenotype. Source: MGI spindle midzone assembly involved in meiosis Inferred from mutant phenotype. Source: MGI
Cellular component	MutLalpha complex Inferred from direct assay. Source: MGI chiasma Inferred from direct assay. Source: MGI male germ cell nucleus Inferred from direct assay. Source: MGI synaptonemal complex Inferred from direct assay. Source: MGI
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro guanine/thymine mispair binding Inferred from genetic interaction. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 760	760	DNA mismatch repair protein Mlh1		PRO_0000178001
Regions
	Region	412 – 654	243	Interaction with EXO1 By similarity
Amino acid modifications
	Modified residue	481	1	Phosphoserine By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q9JK91-1 [UniParc]. Last modified October 1, 2000. Version 1. Checksum: 173C809372A29186	FASTA	760	84,680
	10 20 30 40 50 60 MAFVAGVIRR LDETVVNRIA AGEVIQRPAN AIKEMIENCL DAKSTNIQVV VKEGGLKLIQ 70 80 90 100 110 120 IQDNGTGIRK EDLDIVCERF TTSKLQTFED LASISTYGFR GEALASISHV AHVTITTKTA 130 140 150 160 170 180 DGKCAYRASY SDGKLQAPPK PCAGNQGTLI TVEDLFYNII TRRKALKNPS EEYGKILEVV 190 200 210 220 230 240 GRYSIHNSGI SFSVKKQGET VSDVRTLPNA TTVDNIRSIF GNAVSRELIE VGCEDKTLAF 250 260 270 280 290 300 KMNGYISNAN YSVKKCIFLL FINHRLVESA ALRKAIETVY AAYLPKNTHP FLYLSLEISP 310 320 330 340 350 360 QNVDVNVHPT KHEVHFLHEE SILQRVQQHI ESKLLGSNSS RMYFTQTLLP GLAGPSGEAA 370 380 390 400 410 420 RPTTGVASSS TSGSGDKVYA YQMVRTDSRD QKLDAFLQPV SSLVPSQPQD PAPVRGARTE 430 440 450 460 470 480 GSPERATRED EEMLALPAPA EAAAESENLE RESLMETSDA AQKAAPTSSP GSSRKRHRED 490 500 510 520 530 540 SDVEMVENAS GKEMTAACYP RRRIINLTSV LSLQEEISER CHETLREILR NHSFVGCVNP 550 560 570 580 590 600 QWALAQHQTK LYLLNTTKLS EELFYQILIY DFANFGVLRL SEPAPLFDLA MLALDSPESG 610 620 630 640 650 660 WTEDDGPKEG LAEYIVEFLK KKAEMLADYF SVEIDEEGNL IGLPLLIDSY VPPLEGLPIF 670 680 690 700 710 720 ILRLATEVNW DEEKECFESL SKECAMFYSI RKQYILEEST LSGQQSDMPG STSKPWKWTV 730 740 750 760 EHIIYKAFRS HLLPPKHFTE DGNVLQLANL PDLYKVFERC

References

[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]	"Meiotic pachytene arrest in MLH1-deficient mice." Edelmann W., Cohen P.E., Kane M., Lau K., Morrow B., Bennett S., Umar A., Kunkel T., Cattoretti G., Chaganti R., Pollard J.W., Kolodner R.D., Kucherlapati R. Cell 85:1125-1134(1996) [PubMed: 8674118] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-151.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF250844 mRNA. Translation: AAF64514.1. U60872 , U59881, U59882, U59883, U59884 Genomic DNA. Translation: AAC52672.1.
IPI	IPI00122425.
UniGene	Mm.196006
3D structure databases
HSSP	HSSP built from PDB template 1BKN based on UniProtKB P23367.
ModBase	Search...
PTM databases
PhosphoSite	Q9JK91.
Proteomic databases
PRIDE	Q9JK91.
Genome annotation databases
Ensembl	ENSMUSG00000032498. Mus musculus. [Contig view]
Organism-specific databases
MGI	MGI:101938. Mlh1.
Phylogenomic databases
HOGENOM	Q9JK91.
HOVERGEN	Q9JK91.
Gene expression databases
ArrayExpress	Q9JK91.
Bgee	Q9JK91.
CleanEx	MM_MLH1.
GermOnline	ENSMUSG00000032498. Mus musculus.
Family and domain databases
InterPro	IPR003594. ATP_bd_ATPase. IPR002099. DNA_mismatch_repair. IPR013507. DNA_mismatch_repair_C. IPR014762. DNA_mismatch_repair_CS. IPR011186. DNA_mismatch_repair_MLH1. IPR014763. DNA_mismatch_repair_N. IPR014721. Ribosomal_S5_D2-type_fold. [Graphical view]
Gene3D	G3DSA:3.30.565.10. ATP_bd_ATPase. 1 hit. G3DSA:3.30.230.10. Ribosomal_S5_D2-type_fold. 1 hit.
PANTHER	PTHR10073. DNA_mis_repair. 1 hit. PTHR10073:SF11. MLH1. 1 hit.
Pfam	PF01119. DNA_mis_repair. 1 hit. PF02518. HATPase_c. 1 hit. [Graphical view]
SMART	SM00387. HATPase_c. 1 hit. [Graphical view]
TIGRFAMs	TIGR00585. mutl. 1 hit.
PROSITE	PS00058. DNA_MISMATCH_REPAIR_1. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
SOURCE	Search...

Entry information

Entry name

MLH1_MOUSE

Accession

Primary (citable) accession number: Q9JK91
Secondary accession number(s): Q62454

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 27, 2001
Last sequence update:	October 1, 2000
Last modified:	February 10, 2009
This is version 63 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)