BRCA1/BARD1 site-specific ubiquitylation of nucleosomal H2A is directed by BARD1.
BRCA1 Protein
/ chemistry
Binding Sites
Catalytic Domain
Cryoelectron Microscopy
Histones
/ chemistry
Humans
Lysine
/ chemistry
Models, Molecular
Nucleosomes
/ chemistry
Protein Binding
Reproducibility of Results
Tumor Suppressor Proteins
/ chemistry
Ubiquitin-Conjugating Enzymes
/ chemistry
Ubiquitin-Protein Ligases
/ chemistry
Ubiquitination
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
28
08
2020
accepted:
23
12
2020
pubmed:
17
2
2021
medline:
30
4
2021
entrez:
16
2
2021
Statut:
ppublish
Résumé
Mutations in the E3 ubiquitin ligase RING domains of BRCA1/BARD1 predispose carriers to breast and ovarian cancers. We present the structure of the BRCA1/BARD1 RING heterodimer with the E2 enzyme UbcH5c bound to its cellular target, the nucleosome, along with biochemical data that explain how the complex selectively ubiquitylates lysines 125, 127 and 129 in the flexible C-terminal tail of H2A in a fully human system. The structure reveals that a novel BARD1-histone interface couples to a repositioning of UbcH5c compared to the structurally similar PRC1 E3 ligase Ring1b/Bmi1 that ubiquitylates H2A Lys119 in nucleosomes. This interface is sensitive to both H3 Lys79 methylation status and mutations found in individuals with cancer. Furthermore, NMR reveals an unexpected mode of E3-mediated substrate regulation through modulation of dynamics in the C-terminal tail of H2A. Our findings provide insight into how E3 ligases preferentially target nearby lysine residues in nucleosomes by a steric occlusion and distancing mechanism.
Identifiants
pubmed: 33589814
doi: 10.1038/s41594-020-00556-4
pii: 10.1038/s41594-020-00556-4
pmc: PMC8007219
mid: NIHMS1657757
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Histones
0
Nucleosomes
0
Tumor Suppressor Proteins
0
UBE2D3 protein, human
EC 2.3.2.23
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
BARD1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
268-277Subventions
Organisme : NIH HHS
ID : S10 OD023476
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007270
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM110430
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM088055
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008268
Pays : United States
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