Cooperative nuclear localization sequences lend a novel role to the N-terminal region of MSH6

PLoS One. 2011 Mar 17;6(3):e17907. doi: 10.1371/journal.pone.0017907.


Human mismatch repair proteins MSH2-MSH6 play an essential role in maintaining genetic stability and preventing disease. While protein functions have been extensively studied, the substantial amino-terminal region (NTR*) of MSH6 that is unique to eukaryotic proteins, has mostly evaded functional characterization. We demonstrate that a cluster of three nuclear localization signals (NLS) in the NTR direct nuclear import. Individual NLSs are capable of partially directing cytoplasmic protein into the nucleus; however only cooperative effects between all three NLSs efficiently transport MSH6 into the nucleus. In striking contrast to yeast and previous assumptions on required heterodimerization, human MSH6 does not determine localization of its heterodimeric partner, MSH2. A cancer-derived mutation localized between two of the three NLS significantly decreases nuclear localization of MSH6, suggesting altered protein localization can contribute to carcinogenesis. These results clarify the pending speculations on the functional role of the NTR in human MSH6 and identify a novel, cooperative nuclear localization signal.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Cell Nucleus / metabolism
  • Conserved Sequence / genetics
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Kinetics
  • Models, Biological
  • Molecular Sequence Data
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Nuclear Localization Signals / chemistry
  • Nuclear Localization Signals / metabolism*
  • Point Mutation / genetics
  • Protein Multimerization
  • Recombinant Fusion Proteins / metabolism
  • Reproducibility of Results
  • Sequence Deletion
  • Structure-Activity Relationship
  • Subcellular Fractions / metabolism


  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • Nuclear Localization Signals
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins