INTERACTIONS OF HUMAN HMSH2 WITH HMSH3 AND HMSH2 WITH HMSH6 - EXAMINATION OF MUTATIONS FOUND IN HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

Mutations in the human mismatch repair protein hMSH2 have been found t o cosegregate with hereditary nonpolyposis colorectal cancer (HNPCC). Previous biochemical and physical studies have shown that hMSH2 forms specific mispair binding complexes with hMSH3 and hMSH6. We have furth er characterized these protein interactions by mapping the contact reg ions within the hMSH2 hMSH3 and the hMSH2-hMSH6 heterodimers. We demon strate that there are at least two distinct interaction regions of hMS H2 with hMSH3 and hMSH2 with hMSH6. Interestingly, the interaction reg ions of hMSH2 with either hMSH3 or hMSH6 are identical and there is a coordinated linear orientation of these regions. We examined several m issense alterations of hMSH2 found in HNPCC kindreds that are containe d within the consensus interaction regions. None of these missense mut ations displayed a defect in protein-protein interaction. These data s upport the notion that these HNPCC-associated mutations may affect som e other function of the heterodimeric complexes than simply the static interaction of hMSH2 with hMSH3 or hMSH2 with hMSH6.