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Published on: September 8, 2021
Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1
Yichang Chen1, Haiyun Hu1, Xinci Shang1
1Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
Nature Communications
|July 6, 2026
Summary
Researchers elucidated the structural basis of the interaction between mismatch repair protein MLH1 and nuclease FAN1, crucial for regulating CAG repeat expansion in Huntington's disease.
Area of Science:
- Molecular Biology
- Genetics
- Structural Biology
Background:
- Huntington's disease pathogenesis involves CAG repeat expansion in the mutant huntingtin gene.
- Nuclease FAN1 and mismatch repair protein MLH1 interact to regulate this expansion, but the structural details are unknown.
Purpose of the Study:
- To determine the structural basis of the interaction between human MLH1 and nuclease FAN1.
- To provide a structural framework for understanding the regulation of CAG repeat expansion.
Main Methods:
- Co-immunoprecipitation assays to confirm protein interactions in cells.
- X-ray crystallography to determine the structures of MLH1-FAN1 complexes.
- Analysis of MLH1-FAN1 binding affinities using FAN1-derived peptides.
Main Results:
- The MLH1 C-terminal domain binds FAN1-derived MIP and MIM motifs with similar affinities.
- Crystal structures revealed conserved MLH1-MIP recognition and a novel S3 binding site for MLH1-MIM.
- Mutating key MLH1 residues disrupted FAN1 binding in cellular assays.
Conclusions:
- Established the molecular basis for MLH1-FAN1 recognition.
- Identified novel binding interactions and sites between MLH1 and FAN1.
- Provided structural insights into the regulation of CAG repeat expansion in Huntington's disease.
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