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==Crystal Structure of the MLH1 Protein Bound to the FAN1 Peptide==
<StructureSection load='9woy' size='340' side='right'caption='[[9woy]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9woy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9WOY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WOY FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.28&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9woy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9woy OCA], [https://pdbe.org/9woy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9woy RCSB], [https://www.ebi.ac.uk/pdbsum/9woy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9woy ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MLH1_HUMAN MLH1_HUMAN] Muir-Torre syndrome;Hereditary nonpolyposis colon cancer. Defects in MLH1 are the cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2) [MIM:[https://omim.org/entry/609310 609310]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers 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, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an 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.<ref>PMID:11427529</ref> <ref>PMID:7757073</ref> <ref>PMID:11429708</ref> <ref>PMID:8571956</ref> <ref>PMID:8566964</ref> <ref>PMID:8872463</ref> <ref>PMID:8797773</ref> <ref>PMID:9311737</ref> <ref>PMID:8993976</ref> <ref>PMID:9218993</ref> <ref>PMID:9048925</ref> <ref>PMID:9272156</ref> <ref>PMID:9067757</ref> <ref>PMID:9298827</ref> <ref>PMID:9399661</ref> <ref>PMID:9326924</ref> <ref>PMID:9718327</ref> <ref>PMID:9559627</ref> <ref>PMID:10627141</ref> <ref>PMID:10660333</ref> <ref>PMID:10671064</ref> <ref>PMID:9833759</ref> <ref>PMID:10375096</ref> <ref>PMID:9927034</ref> <ref>PMID:10323887</ref> <ref>PMID:10480359</ref> <ref>PMID:10598809</ref> <ref>PMID:10386556</ref> <ref>PMID:10413423</ref> <ref>PMID:10777691</ref> <ref>PMID:10713887</ref> <ref>PMID:10882759</ref> <ref>PMID:12132870</ref> <ref>PMID:11726306</ref> <ref>PMID:11139242</ref> <ref>PMID:11748856</ref> <ref>PMID:12095971</ref> <ref>PMID:12373605</ref> <ref>PMID:11781295</ref> <ref>PMID:11839723</ref> <ref>PMID:11793442</ref> <ref>PMID:11754112</ref> <ref>PMID:12200596</ref> <ref>PMID:11870161</ref> <ref>PMID:12362047</ref> <ref>PMID:12658575</ref> <ref>PMID:12655562</ref> <ref>PMID:14635101</ref> <ref>PMID:15139004</ref> <ref>PMID:15365995</ref> <ref>PMID:15365996</ref> <ref>PMID:14961575</ref> <ref>PMID:15064764</ref> <ref>PMID:16083711</ref> <ref>PMID:16451135</ref> <ref>PMID:17510385</ref> <ref>PMID:17301300</ref> <ref>PMID:18561205</ref>   Defects in MLH1 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:[https://omim.org/entry/276300 276300]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.<ref>PMID:11427529</ref> <ref>PMID:7661930</ref> <ref>PMID:17440981</ref>   Defects in MLH1 are a cause of Muir-Torre syndrome (MRTES) [MIM:[https://omim.org/entry/158320 158320]. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.<ref>PMID:8751876</ref>   Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.<ref>PMID:11369138</ref>   Defects in MLH1 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:[https://omim.org/entry/608089 608089].  Note=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.
== Function ==
[https://www.uniprot.org/uniprot/MLH1_HUMAN MLH1_HUMAN] 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.<ref>PMID:16873062</ref> <ref>PMID:18206974</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Huntington's disease is driven by CAG repeat expansion in the mutant huntingtin gene. Nuclease FAN1 and mismatch repair protein MLH1 regulate repeat expansion through direct interaction, but the underlying structural basis remains unclear. Here, we show that the MLH1 C-terminal domain binds to FAN1-derived peptides containing either the MIP or MIM motif with comparable affinities. Crystal structures of this domain bound to each motif provide structural insights into human MLH1-FAN1 interaction, revealing a conserved mechanism for FAN1-MIP recognition and a previously unrecognized binding site on MLH1, termed the S3 site, for FAN1-MIM engagement. Co-immunoprecipitation assays confirmed that mutation of key MLH1 residues disrupts FAN1 binding in cells. These findings establish the molecular basis of MLH1-FAN1 recognition and provide a structural framework for understanding the regulation of CAG repeat expansion in Huntington's disease.

Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1.,Chen Y, Hu H, Shang X, Fishwick KM, Greco G, Xiao Q, Zhou Y, Huang Q, Jiang T, Huang X, Wang G, Zhen X, Xu G, Qin S, Sartori AA, Liu Y Nat Commun. 2026 Jul 6. doi: 10.1038/s41467-026-74991-0. PMID:42409804<ref>PMID:42409804</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9woy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen YC]]
[[Category: Liu YL]]
[[Category: Shang XC]]