PXD014282

PXD014282 is an original dataset announced via ProteomeXchange.

Title	Structure of the Fanconi anaemia monoubiquitin ligase complex
Description	The Fanconi Anemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks. Genetic inactivation of this pathway impairs development, prevents blood production and promotes cancer. The key molecular step in the FA pathway is the monoubiquitination of a heterodimer of FANCI-FANCD2 by the FA core complex - a megadalton multiprotein E3 ubiquitin ligase. Monoubiquitinated FANCI-FANCD2 then activates a pathway to remove the DNA crosslink. Lack of molecular insight into the FA core complex limits a detailed explanation of how this vital DNA repair pathway functions. Here we reconstituted an active, recombinant FA core complex, and used electron cryo-microscopy (cryo-EM) and mass spectrometry to determine its overall structure. The FA core complex is comprised of a central symmetric dimer of the FANCB and FAAP100 subunits, flanked by two copies of the RING finger protein, FANCL. This acts as a scaffold to assemble the remaining five subunits, resulting in an extended asymmetric structure. The two FANCL subunits are positioned at opposite ends of the complex in an unusual asymmetric arrangement, distinct from other E3 ligases. We propose that each of the two FANCL subunits play unique roles within the complex – one is a structural component while the other monoubiquitinates FANCD2. The cryo-EM structure of the FA core complex, supported by crosslinking mass spectrometry and native mass spectrometry, therefore provides a foundation for a detailed understanding of this fundamental DNA repair pathway.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:57:04.057.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Francis O'Reilly
SpeciesList	scientific name: Gallus gallus (Chicken); NCBI TaxID: 9031;
ModificationList	carbamoylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-06-18 01:35:05	ID requested
1	2019-10-16 02:05:36	announced
2	2019-11-08 00:42:46	announced	2019-11-08: Updated publication reference for PubMed record(s): 31666700.
3	2019-11-27 06:00:00	announced	2019-11-27: Updated project metadata.
⏵ 4	2024-10-22 04:57:04	announced	2024-10-22: Updated project metadata.

10.1038/s41586-019-1703-4;

Shakeel S, Rajendra E, Alc, ó, n P, O'Reilly F, Chorev DS, Maslen S, Degliesposti G, Russo CJ, He S, Hill CH, Skehel JM, Scheres SHW, Patel KJ, Rappsilber J, Robinson CV, Passmore LA, Structure of the Fanconi anaemia monoubiquitin ligase complex. Nature, 575(7781):234-237(2019) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: Fanconi anemia monoubiquitin ligase, human, crosslinking MS, EM, Electron microscopy, CLMS

Juri Rappsilber
contact affiliation	Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, Scotland, United Kingdom
contact email	juri.rappsilber@tu-berlin.de
lab head
Francis O'Reilly
contact affiliation	TU Berlin
contact email	oreilly@tu-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014282
     1. Label: PRIDE project
     2. Name: Structure of the Fanconi anaemia monoubiquitin ligase complex