Prediction-based threading of the hMSH2 DNA mismatch repair protein.
Mutations in the genes whose products participate in DNA mismatch repair underlie the increased risk of cancer in families with hereditary nonpolyposis colon carcinoma. Mutations in hMSH2 account for approximately 50% of the mutations found in these families. We sought to predict the 3-dimensional structure of hMSH2 by identifying structural homologues using prediction-based threading and by computer modeling using information from these putative structurally related proteins. Prediction-based threading identified three candidate structural homologues: glycogen phosphorylase (gpb), a 70 kDa soluble lytic transglycosylase, and ribonucleotide reductase protein R1. An independent approach utilizing a potential-based threading program also identified gpb as a structural homologue. The models based on the structures of these proteins suggest that the ATP binding domain and helix-turn-helix domain are exposed on the outside of the protein. All known bacterial MutS and hMSH2 mutations appear to be clustered in similar vicinities in the theoretical models of hMSH2; the major site is within the ATP binding domain and near the carboxyl-terminal end, whereas a smaller number map to the region coding for exon 5 and the amino-terminal domain. All point mutations also appear to affect amino acids that are exposed on the outside surface of the protein.
de las Alas
M M
MM
Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla 92093-0058, USA.
de Bruin
R A
RA
Ten Eyck
L
L
Los
G
G
Howell
S B
SB
D001426:Bacterial Proteins / Q000737:chemistry; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D003198:Computer Simulation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry*; D029968:Escherichia coli Proteins; D006026:Glycoside Hydrolases; D016695:Glycosyltransferases / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D051718:MutS Homolog 2 Protein; D009154:Mutation; D006005:Phosphorylases / Q000737:chemistry; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D012264:Ribonucleotide Reductases / Q000737:chemistry
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D011518:Proto-Oncogene Proteins; D012264:Ribonucleotide Reductases; D016695:Glycosyltransferases; D006005:Phosphorylases; D006026:Glycoside Hydrolases; C085428:slt protein, E coli; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein