7ay1 | pdb_00007ay1

Cryo-EM structure of USP1-UAF1 bound to mono-ubiquitinated FANCD2, and FANCI

Structural highlights

7ay1 is a 7 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	DN, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FANCI_HUMAN] Fanconi anemia. The disease is caused by variants affecting the gene represented in this entry.

Function

[FANCI_HUMAN] Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA repair sites. Required for maintenance of chromosomal stability. Specifically binds branched DNA: binds both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). Participates in S phase and G2 phase checkpoint activation upon DNA damage.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

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.

Structural basis of FANCD2 deubiquitination by USP1-UAF1.,Rennie ML, Arkinson C, Chaugule VK, Toth R, Walden H Nat Struct Mol Biol. 2021 Apr;28(4):356-364. doi: 10.1038/s41594-021-00576-8., Epub 2021 Apr 1. PMID:33795880^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007 Apr 20;129(2):289-301. doi: 10.1016/j.cell.2007.03.009. Epub 2007 Apr , 5. PMID:17412408 doi:https://dx.doi.org/10.1016/j.cell.2007.03.009
↑ Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D, Mohan S, Schindler D, Arwert F, Pals G, Mathew CG, Waisfisz Q, de Winter JP, Joenje H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29(3):211-8. PMID:17452773
↑ Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007 Jun;14(6):564-7. Epub 2007 Apr 25. PMID:17460694 doi:https://dx.doi.org/nsmb1252
↑ Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:https://dx.doi.org/10.1016/j.molcel.2008.12.003
↑ Rennie ML, Arkinson C, Chaugule VK, Toth R, Walden H. Structural basis of FANCD2 deubiquitination by USP1-UAF1. Nat Struct Mol Biol. 2021 Apr;28(4):356-364. doi: 10.1038/s41594-021-00576-8., Epub 2021 Apr 1. PMID:33795880 doi:https://dx.doi.org/10.1038/s41594-021-00576-8

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OCA

[1] Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007 Apr 20;129(2):289-301. doi: 10.1016/j.cell.2007.03.009. Epub 2007 Apr , 5. PMID:17412408 doi:https://dx.doi.org/10.1016/j.cell.2007.03.009

[2] Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D, Mohan S, Schindler D, Arwert F, Pals G, Mathew CG, Waisfisz Q, de Winter JP, Joenje H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29(3):211-8. PMID:17452773

[3] Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007 Jun;14(6):564-7. Epub 2007 Apr 25. PMID:17460694 doi:https://dx.doi.org/nsmb1252

[4] Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:https://dx.doi.org/10.1016/j.molcel.2008.12.003

[5] Rennie ML, Arkinson C, Chaugule VK, Toth R, Walden H. Structural basis of FANCD2 deubiquitination by USP1-UAF1. Nat Struct Mol Biol. 2021 Apr;28(4):356-364. doi: 10.1038/s41594-021-00576-8., Epub 2021 Apr 1. PMID:33795880 doi:https://dx.doi.org/10.1038/s41594-021-00576-8

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7ay1 | pdb_00007ay1

Cryo-EM structure of USP1-UAF1 bound to mono-ubiquitinated FANCD2, and FANCI

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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Proteopedia Page Contributors and Editors (what is this?)

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