Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1.

Authors

Yichang Chen, Haiyun Hu, Xinci Shang, Keri M Fishwick, Giada Greco, Qin Xiao, Yinhao Zhou, Qiuyan Huang, Tao Jiang, Xiaolei Huang, Guanghui Wang, Xuechu Zhen, Guoqiang Xu, Su Qin, Alessandro A Sartori, Yanli Liu

Published in

Nature communications. Jul 06, 2026. Epub Jul 06, 2026.

Abstract

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.

PMID:
42409804
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

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