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Papers In Press, published online ahead of print November 8, 2002
Biochemistry Dept., University of Alberta, Edmonton, Alberta T6G-2H7
Corresponding Author: mark.glover{at}ualberta.ca
The integrity of the C-terminal, BRCT repeat region is critical for BRCA1 tumour suppressor function, however the molecular details of how a number of clinically derived BRCT missense mutations affect BRCA1 function remain largely unknown. Here we assess the structural response of the BRCT tandem repeat domain to a well-characterized, cancer-associated single amino acid substitution, Met1775 to Arg1775. The structure of BRCT-M1775R reveals that the mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the two BRCT repeats contribute to the conformational instability of BRCT-M1775R. Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explains the pleiotropic molecular and genetic defects associated with the BRCA1- M1775R protein.
J. Biol. Chem, 10.1074/jbc.M210019200
Submitted on September 30, 2002
Revised on November 8, 2002
Accepted on November 7, 2002
Structural consequences of a cancer-causing BRCA1-BRCT missense mutation
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