Conformational flexibility and oligomerization of BRCA2 regions induced by RAD51 interaction.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
25 09 2020
25 09 2020
Historique:
accepted:
07
08
2020
revised:
15
07
2020
received:
07
11
2019
pubmed:
14
8
2020
medline:
11
11
2020
entrez:
14
8
2020
Statut:
ppublish
Résumé
BRCA2 is a key breast cancer associated protein that is predicted to have interspersed regions of intrinsic disorder. Intrinsic disorder coupled with large size likely allows BRCA2 to sample a broad range of conformational space. We expect that the resulting dynamic arrangements of BRCA2 domains are a functionally important aspect of its role in homologous recombination DNA repair. To determine the architectural organization and the associated conformational landscape of BRCA2, we used scanning force microscopy based single molecule analyses to map the flexible regions of the protein and characterize which regions influence oligomerization. We show that the N- and the C-terminal regions are the main flexible regions. Both of these regions also influence BRCA2 oligomerization and interaction with RAD51. In the central Brc repeat region, Brc 1-4 and Brc 5-8 contribute synergistically to BRCA2 interaction with RAD51. We also analysed several single amino acid changes that are potentially clinically relevant and found one, the variant of F1524V, which disrupts key interactions and alters the conformational landscape of the protein. We describe the overall conformation spectrum of BRCA2, which suggests that dynamic structural transitions are key features of its biological function, maintaining genomic stability.
Identifiants
pubmed: 32785644
pii: 5891569
doi: 10.1093/nar/gkaa648
pmc: PMC7515699
doi:
Substances chimiques
BRCA2 Protein
0
BRCA2 protein, human
0
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9649-9659Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
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