7AY2

Crystal structure of truncated USP1-UAF1 reacted with ubiquitin-prg

Summary for 7AY2

• Entry DOI: 10.2210/pdb7ay2/pdb
• Related: 7AY0
• Descriptor: WD repeat-containing protein 48, Ubiquitin carboxyl-terminal hydrolase 1, Polyubiquitin-B, ... (5 entities in total)
• Functional Keywords: deubiquitination, specificity, dna repair, fanconi anemia, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 233917.09

Authors

Arkinson, C.,Rennie, M.L.,Walden, H. (deposition date: 2020-11-10, release date: 2021-03-24, Last modification date: 2024-02-07)

Primary citation

Rennie, M.L.,Arkinson, C.,Chaugule, V.K.,Toth, R.,Walden, H.
Structural basis of FANCD2 deubiquitination by USP1-UAF1.
Nat.Struct.Mol.Biol., 28:356-364, 2021

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 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.

PubMed: 33795880
DOI: 10.1038/s41594-021-00576-8

Experimental method

X-RAY DIFFRACTION (3.2 Å)