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J. Biol. Chem., Vol. 278, Issue 4, 2630-2635, January 24, 2003
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From the Department of Biochemistry, 437 Medical Sciences Building,
University of Alberta, Edmonton T6G 2H7, Canada
The integrity of the carboxyl-terminal BRCT
repeat region is critical for BRCA1 tumor 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, Met-1775 
Arg-1775. 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 explain the pleiotropic molecular and
genetic defects associated with the BRCA1-M1775R protein.
The atomic coordinates and the structure factors (code 1N5O) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
To whom correspondence should be addressed. Tel.: 1-780-492-2136;
Fax: 1-780-492-0886; E-mail: mark.glover@ualberta.ca.
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