MLH3

Protein identityUniProt · HPA

UniProt accession

Q9UHC1

Gene

MLH3

Ensembl

ENSG00000119684

Chromosome

14

Canonical length

1453 aa

Protein class

Disease related genes, Human disease related genes, Plasma proteins, Predicted intracellular proteins

Subcellular location

Nucleoplasm

OverviewNCBI Gene

This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

Canonical amino-acid sequenceUniProt

1453 residues, UniProt reviewed canonical sequence.

>Q9UHC1|MLH3
     1  MIKCLSVEVQ AKLRSGLAIS SLGQCVEELA LNSIDAEAKC VAVRVNMETF QVQVIDNGFG
    61  MGSDDVEKVG NRYFTSKCHS VQDLENPRFY GFRGEALANI ADMASAVEIS SKKNRTMKTF
   121  VKLFQSGKAL KACEADVTRA SAGTTVTVYN LFYQLPVRRK CMDPRLEFEK VRQRIEALSL
   181  MHPSISFSLR NDVSGSMVLQ LPKTKDVCSR FCQIYGLGKS QKLREISFKY KEFELSGYIS
   241  SEAHYNKNMQ FLFVNKRLVL RTKLHKLIDF LLRKESIICK PKNGPTSRQM NSSLRHRSTP
   301  ELYGIYVINV QCQFCEYDVC MEPAKTLIEF QNWDTLLFCI QEGVKMFLKQ EKLFVELSGE
   361  DIKEFSEDNG FSLFDATLQK RVTSDERSNF QEACNNILDS YEMFNLQSKA VKRKTTAENV
   421  NTQSSRDSEA TRKNTNDAFL YIYESGGPGH SKMTEPSLQN KDSSCSESKM LEQETIVASE
   481  AGENEKHKKS FLEHSSLENP CGTSLEMFLS PFQTPCHFEE SGQDLEIWKE STTVNGMAAN
   541  ILKNNRIQNQ PKRFKDATEV GCQPLPFATT LWGVHSAQTE KEKKKESSNC GRRNVFSYGR
   601  VKLCSTGFIT HVVQNEKTKS TETEHSFKNY VRPGPTRAQE TFGNRTRHSV ETPDIKDLAS
   661  TLSKESGQLP NKKNCRTNIS YGLENEPTAT YTMFSAFQEG SKKSQTDCIL SDTSPSFPWY
   721  RHVSNDSRKT DKLIGFSKPI VRKKLSLSSQ LGSLEKFKRQ YGKVENPLDT EVEESNGVTT
   781  NLSLQVEPDI LLKDKNRLEN SDVCKITTME HSDSDSSCQP ASHILNSEKF PFSKDEDCLE
   841  QQMPSLRESP MTLKELSLFN RKPLDLEKSS ESLASKLSRL KGSERETQTM GMMSRFNELP
   901  NSDSSRKDSK LCSVLTQDFC MLFNNKHEKT ENGVIPTSDS ATQDNSFNKN SKTHSNSNTT
   961  ENCVISETPL VLPYNNSKVT GKDSDVLIRA SEQQIGSLDS PSGMLMNPVE DATGDQNGIC
  1021  FQSEESKARA CSETEESNTC CSDWQRHFDV ALGRMVYVNK MTGLSTFIAP TEDIQAACTK
  1081  DLTTVAVDVV LENGSQYRCQ PFRSDLVLPF LPRARAERTV MRQDNRDTVD DTVSSESLQS
  1141  LFSEWDNPVF ARYPEVAVDV SSGQAESLAV KIHNILYPYR FTKGMIHSMQ VLQQVDNKFI
  1201  ACLMSTKTEE NGEAGGNLLV LVDQHAAHER IRLEQLIIDS YEKQQAQGSG RKKLLSSTLI
  1261  PPLEITVTEE QRRLLWCYHK NLEDLGLEFV FPDTSDSLVL VGKVPLCFVE REANELRRGR
  1321  STVTKSIVEE FIREQLELLQ TTGGIQGTLP LTVQKVLASQ ACHGAIKFND GLSLQESCRL
  1381  IEALSSCQLP FQCAHGRPSM LPLADIDHLE QEKQIKPNLT KLRKMAQAWR LFGKAECDTR
  1441  QSLQQSMPPC EPP

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against MLH3 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.51

Highest tissue expression

12 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about MLH3.

Disease | AllUniProt

Conditions MLH3 is implicated in, by any mechanism.

• Hereditary non-polyposis colorectal cancer 7 (HNPCC7) MIM:614385
• Colorectal cancer (CRC) MIM:114500

Disease | GeneticClinVar

24 pathogenic / likely-pathogenic of 3,345 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Colorectal cancer, hereditary nonpolyposis, type 7
• Colorectal cancer
• Endometrial carcinoma

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.59

gnomAD pLI

0

gnomAD missense Z

0.74

DepMap mean gene effect

-0.15

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• female meiosis I
• intracellular protein localization
• male meiotic nuclear division
• mismatch repair
• reciprocal meiotic recombination
• synaptonemal complex assembly

Molecular functions

• ATP binding
• ATP hydrolysis activity
• ATP-dependent DNA damage sensor activity
• centromeric DNA binding
• chromatin binding
• mismatched DNA binding
• satellite DNA binding

Cellular components

• chiasma
• male germ cell nucleus
• mismatch repair complex
• nucleoplasm
• nucleus
• synaptonemal complex

Protein domainsUniProt · Pfam · InterPro

• DNA mismatch repair protein MutL/Mlh/PMS
• DNA mismatch repair protein, S5 domain 2-like
• Small ribosomal subunit protein uS5 domain 2-type fold, subgroup
• DNA mismatch repair, conserved site
• MutL, C-terminal, dimerisation
• Ribosomal protein uS5 domain 2-type superfamily
• Histidine kinase/HSP90-like ATPase superfamily
• MutL, C-terminal domain superfamily
• DNA mismatch repair protein MutL/Mlh/Pms-like
• MutL, C-terminal domain, dimerisation subdomain
• MutL, C-terminal domain, regulatory subdomain
• DNA mismatch repair protein, C-terminal domain
• MutL C terminal dimerisation domain
• Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase

KeywordsUniProt

• DNA damage
• DNA repair
• Hereditary nonpolyposis colorectal cancer
• Nucleus

InteractionsUniProt · HPA

Protein binding partners of MLH3 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• FAN1
• MLH1