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Structural consequences of a cancer-causing BRCA1-BRCT missense mutation

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Title: Structural consequences of a cancer-causing BRCA1-BRCT missense mutation
Author: Williams, R. S.; Glover, J. N.
Abstract: 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.
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Publisher: American Society for Biochemistry and Molecular Biology
URI: http://hdl.handle.net/1807.1/162
Date: 2003-01

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