PXD078865-1

PXD078865 is an original dataset announced via ProteomeXchange.

Title	FAF1 and FAF2 enhance human p97-UFD1-NPL4 complex unfoldase activity enabling rational design of p97 activators - Crosslinking mass spec data
Description	VCP/p97 is an AAA+ ATPase that, together with its cofactors UFD1-NPL4 (p97-UN), binds and unfolds ubiquitylated substrates to maintain cellular homeostasis. The human p97-UN complex associates with additional cofactors, but how these cofactors modulate p97-UN activity is not fully understood. We screen for cofactors that enhance p97-UN activity and identify FAF2 as the strongest activator. Using biochemical and structural approaches, we show how FAF2 engages p97-UN and polyubiquitin to promote unfolding. We define a conserved activation motif in FAF2 that contacts both UFD1 and the ubiquitin proximal to the initiator, stabilizing and initiating unfolding in a UFD1-dependent manner. We leverage the features of FAF2 AM to engineer de novo proteins that potently enhance unfolding, providing a rational strategy to boost p97 activity. Our findings reveal how cofactors can provide additional adaptive control, fine-tuning human p97 activity to unfold challenging substrates and those modified with short ubiquitin chains. The information here relates to the cross-linking mass spectrometry data portion of the project.
HostingRepository	PRIDE
AnnounceDate	2026-07-28
AnnouncementXML	Submission_2026-07-28_04:55:36.945.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ian Kelsall
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2026-05-26 14:27:57	ID requested
⏵ 1	2026-07-28 04:55:37	announced

Dataset with its publication pending

submitter keyword: ATPase,XL-MS, FAF2, UFD1, VCP, NPL4, p97

Yogesh Kulathu
contact affiliation	MRC Protein Phosphorylation and Ubiquitylation Unit, Faculty of Life Sciences, University of Dundee, UK
contact email	y.kulathu@dundee.ac.uk
lab head
Ian Kelsall
contact affiliation	MRC Protein & Ubiquitylation Unit, University of Dundee
contact email	irkelsall@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD078865
     1. Label: PRIDE project
     2. Name: FAF1 and FAF2 enhance human p97-UFD1-NPL4 complex unfoldase activity enabling rational design of p97 activators - Crosslinking mass spec data