The N terminus of Saccharomyces cerevisiae Msh6 is an unstructured tether to PCNA.

The eukaryotic MutS homolog complexes, Msh2-Msh6 and Msh2-Msh3, recognize mismatched bases in DNA during mismatch repair (MMR). The eukaryote-specific N-terminal regions (NTRs) of Msh6 and Msh3 have not been characterized other than by demonstrating that they contain an N-terminal PCNA-interacting motif. Here we have demonstrated genetically that the NTR of Msh6 has an important role in MMR that is partially redundant with PCNA binding. Small-angle X-ray scattering (SAXS) was used to determine the solution structure of the complex of PCNA with Msh2-Msh6 and with the isolated Msh6 NTR, revealing that the Msh6 NTR is a natively disordered domain that forms an extended tether between Msh6 and PCNA. Moreover, computational analysis of PCNA-interacting motifs in the S. cerevisiae proteome indicated that flexible linkers are a common theme for PCNA-interacting proteins that may serve to localize these binding partners without tightly restraining them to the immediate vicinity of PCNA.