BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions.
J Biol Chem
; 276(44): 41399-406, 2001 Nov 02.
Article
en En
| MEDLINE
| ID: mdl-11526114
ABSTRACT
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína BRCA1
/
Predisposición Genética a la Enfermedad
/
Mutación Missense
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2001
Tipo del documento:
Article
País de afiliación:
Estados Unidos