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

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dc.contributor.author Williams, R. S. en_US
dc.contributor.author Glover, J. N. en_US
dc.date.accessioned 2006-06-22T14:16:35Z
dc.date.available 2006-06-22T14:16:35Z
dc.date.issued 2003-01 en_US
dc.identifier.citation J Biol Chem 278, 2630-5 (2003) en_US
dc.identifier.uri http://hdl.handle.net/1807.1/162
dc.description This article is hosted on a website external to the CBCRA Open Access Archive. Selecting “View/Open” below will launch the full-text article in another browser window.
dc.description.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. en_US
dc.description.provenance Made available in DSpace on 2006-06-22T14:16:35Z (GMT). No. of bitstreams: 1 Williams.2003.2630.html: 411 bytes, checksum: edccb734909548255e460dd409f996f0 (MD5) Previous issue date: 2003-01 en
dc.format.extent 411 bytes
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dc.language.iso en en_US
dc.publisher American Society for Biochemistry and Molecular Biology en_US
dc.relation.uri http://www.asbmb.org/ en_US
dc.title Structural consequences of a cancer-causing BRCA1-BRCT missense mutation en_US
dc.type Article en_US

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