PREDICTION-BASED THREADING OF THE HMSH2 DNA MISMATCH REPAIR PROTEIN

Citation
Mm. Delasalas et al., PREDICTION-BASED THREADING OF THE HMSH2 DNA MISMATCH REPAIR PROTEIN, The FASEB journal, 12(9), 1998, pp. 653-663
Citations number
68
Categorie Soggetti
Biology,Biology,"Cell Biology
Journal title
ISSN journal
08926638
Volume
12
Issue
9
Year of publication
1998
Pages
653 - 663
Database
ISI
SICI code
0892-6638(1998)12:9<653:PTOTHD>2.0.ZU;2-E
Abstract
Mutations in the genes whose products participate in DNA mismatch repa ir underlie the increased risk of cancer in families with. hereditary nonpolyposis colon carcinoma. Mutations in hMSH2 account for approxima tely 50% of the mutations found in these families, We sought to predic t the 3-dimensional structure of hMSH2 by identifying structural homol ogues using prediction-based threading and by computer modeling using information from these putative structurally related proteins. Predict ion-based threading identified three candidate structural homologues: glycogen phosphorylase (gpb), a 70 kDa soluble lyric transglycosylase, and ribonucleotide reductase protein R1. An independent approach util izing a potential-based threading program also identified gpb as a str uctural homologue. The models based on the structures of these protein s suggest that the ATP binding domain and helix-turn-helix domain are exposed on the outside of the protein, All known bacterial MutS and hM SH2 mutations appear to be clustered in similar vicinities in the theo retical models of hMSH2; the major site is within the ATP binding doma in 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 o utside surface of the protein.