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Structure of the FA core ubiquitin ligase closing the ID clamp on DNA.
- Source :
-
Nature structural & molecular biology [Nat Struct Mol Biol] 2021 Mar; Vol. 28 (3), pp. 300-309. Date of Electronic Publication: 2021 Mar 08. - Publication Year :
- 2021
-
Abstract
- The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand crosslinks. Central to the pathway is the FA core complex, a ubiquitin ligase of nine subunits that monoubiquitinates the FANCI-FANCD2 (ID) DNA clamp. The 3.1 Å structure of the 1.1-MDa human FA core complex, described here, reveals an asymmetric assembly with two copies of all but the FANCC, FANCE and FANCF subunits. The asymmetry is crucial, as it prevents the binding of a second FANCC-FANCE-FANCF subcomplex that inhibits the recruitment of the UBE2T ubiquitin conjugating enzyme, and instead creates an ID binding site. A single active site then ubiquitinates FANCD2 and FANCI sequentially. We also present the 4.2-Å structures of the human core-UBE2T-ID-DNA complex in three conformations captured during monoubiquitination. They reveal the core-UBE2T complex remodeling the ID-DNA complex, closing the clamp on the DNA before ubiquitination. Monoubiquitination then prevents clamp opening after release from the core.
- Subjects :
- Binding Sites
Cryoelectron Microscopy
DNA chemistry
DNA ultrastructure
Fanconi Anemia Complementation Group C Protein metabolism
Fanconi Anemia Complementation Group D2 Protein metabolism
Fanconi Anemia Complementation Group E Protein metabolism
Fanconi Anemia Complementation Group F Protein metabolism
Fanconi Anemia Complementation Group Proteins ultrastructure
HEK293 Cells
Humans
Models, Molecular
Multienzyme Complexes ultrastructure
Reproducibility of Results
Ubiquitin-Conjugating Enzymes metabolism
Ubiquitin-Protein Ligases ultrastructure
Ubiquitination
Ubiquitins metabolism
DNA metabolism
Fanconi Anemia Complementation Group Proteins chemistry
Fanconi Anemia Complementation Group Proteins metabolism
Multienzyme Complexes chemistry
Multienzyme Complexes metabolism
Ubiquitin-Protein Ligases chemistry
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1545-9985
- Volume :
- 28
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Nature structural & molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 33686268
- Full Text :
- https://doi.org/10.1038/s41594-021-00568-8