1N5O

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

(2003) J Biol Chem 278: 2630-2635

• PubMed: 12427738 Search on PubMed
• DOI: https://doi.org/10.1074/jbc.M210019200
• Primary Citation of Related Structures:  
  1N5O


• PubMed 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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Organizational Affiliation: 

Department of Biochemistry, 437 Medical Sciences Building, University of Alberta, Edmonton T6G 2H7, Canada.