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bioRxiv · 10.1101/475152

Intrinsically disordered regions regulate both catalytic and non-catalytic activities of the MutLα mismatch repair complex.

Kim, Y.·Furman, C. M.·Manhart, C. M.·Alani, E.·Finkelstein, I. J.
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Abstract

Intrinsically disordered regions (IDRs) are present in at least 30% of the eukaryotic proteome and are enriched in chromatin-associated proteins. Using a combination of genetics, biochemistry, and single-molecule biophysics, we characterize how IDRs regulate the functions of the yeast MutL (Mlh1-Pms1) mismatch repair (MMR) complex. Shortening or scrambling the IDRs in both subunits ablates MMR in vivo. Mlh1-Pms1 complexes with shorter IDRs that disrupt MMR retain wild-type DNA binding affinity but are impaired for diffusion on both naked and nucleosome-coated DNA. Moreover, the IDRs also regulate the ATP hydrolysis and nuclease activities that are encoded in the structured N- and C-terminal domains of the complex. This combination of phenotypes underlies the catastrophic MMR defect seen with the mutant MutL in vivo. More broadly, this work highlights an unanticipated multi-functional role for IDRs in regulating both facilitated diffusion on chromatin and nucleolytic processing of a DNA substrate.

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Kim, Y., Furman, C. M., Manhart, C. M., Alani, E., Finkelstein, I. J.. 2018-11-20. Intrinsically disordered regions regulate both catalytic and non-catalytic activities of the MutLα mismatch repair complex.. https://doi.org/10.1101/475152

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