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

Nucleic Acids Res. 2019 Feb 28;47(4):1823-1835. doi: 10.1093/nar/gky1244.


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 MutLα (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 adenosine triphosphate 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 MutLα 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Chromatin / genetics
  • DNA Mismatch Repair / genetics
  • DNA-Binding Proteins / genetics
  • Intrinsically Disordered Proteins / genetics*
  • Multiprotein Complexes / genetics
  • MutL Protein Homolog 1 / genetics*
  • MutL Proteins / genetics*
  • Mutation
  • Proteome / genetics
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics*


  • Chromatin
  • DNA-Binding Proteins
  • Intrinsically Disordered Proteins
  • MLH1 protein, S cerevisiae
  • Multiprotein Complexes
  • PMS1 protein, S cerevisiae
  • Proteome
  • Saccharomyces cerevisiae Proteins
  • MutL Protein Homolog 1
  • MutL Proteins