BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions.

Cancer-predisposing missense mutations in the RING domain of BRCA1 primarily target Zn(2+)-liganding residues. Here we report on the structural consequences of such mutations introduced into the second Zn(2+) site (Site II) of the BRCA1 RING domain and their effect on the interaction with the BARD1 RING domain. Each of the ...
BRCA1 Site II mutants still interact and form a stable heterodimer with BARD1. Limited proteolysis of BRCA1/BARD1 complexes, monitored by matrix-assisted laser desorption ionization time-of-flight spectrometry, show that the mutations cause a local structural perturbation that is primarily confined to the second Zn(2+) binding loop of the BRCA1 subunit. These findings are consistent with the structure of the BRCA1/BARD1 heterodimer, which shows this region is well removed from the helices required for dimerization with BARD1. Instead, the mutations alter a region of BRCA1 that appears to be required for interaction with ubiquitin-conjugating enzymes.
Mesh Terms:
BRCA1 Protein, Dimerization, Genetic Predisposition to Disease, Humans, Hydrolysis, Models, Molecular, Mutation, Missense, Protein Binding, Protein Conformation, Spectrometry, Mass, Electrospray Ionization, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Zinc
J. Biol. Chem.
Date: Nov. 02, 2001
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