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Title | Structural basis of FANCD2 deubiquitination by USP1-UAF1. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 28, Issue 4, Page 356-364, Year 2021 |
Publish date | Apr 1, 2021 |
![]() | Martin L Rennie / Connor Arkinson / Viduth K Chaugule / Rachel Toth / Helen Walden / ![]() |
PubMed Abstract | Ubiquitin-specific protease 1 (USP1) acts together with the cofactor UAF1 during DNA repair processes to specifically remove monoubiquitin signals. One substrate of the USP1-UAF1 complex is the ...Ubiquitin-specific protease 1 (USP1) acts together with the cofactor UAF1 during DNA repair processes to specifically remove monoubiquitin signals. One substrate of the USP1-UAF1 complex is the monoubiquitinated FANCI-FANCD2 heterodimer, which is involved in the repair of DNA interstrand crosslinks via the Fanconi anemia pathway. Here we determine structures of human USP1-UAF1 with and without ubiquitin and bound to monoubiquitinated FANCI-FANCD2. The crystal structures of USP1-UAF1 reveal plasticity in USP1 and key differences to USP12-UAF1 and USP46-UAF1, two related proteases. A cryo-EM reconstruction of USP1-UAF1 in complex with monoubiquitinated FANCI-FANCD2 highlights a highly orchestrated deubiquitination process, with USP1-UAF1 driving conformational changes in the substrate. An extensive interface between UAF1 and FANCI, confirmed by mutagenesis and biochemical assays, provides a molecular explanation for the requirement of both proteins, despite neither being directly involved in catalysis. Overall, our data provide molecular details of USP1-UAF1 regulation and substrate recognition. |
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Methods | EM (single particle) / X-ray diffraction |
Resolution | 3.2 - 3.7 Å |
Structure data | EMDB-11934, PDB-7ay1: ![]() PDB-7ay0: ![]() PDB-7ay2: |
Chemicals | ![]() ChemComp-ZN: ![]() ChemComp-AYE: |
Source |
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![]() | HYDROLASE / deubiquitination / specificity / DNA repair / Fanconi Anemia |