FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.

Authors

Pritha Dasgupta, Ian R Kelsall, Gaurav Anand, Anna Pérez-Ràfols, Thomas A Jowitt, Axel Knebel, Robert Gourlay, Glenn R Masson, Yogesh Kulathu

Published in

The EMBO journal. Aug 15, 2026. Epub Aug 15, 2026.

Abstract

VCP/p97 is an AAA+ ATPase that, together with its cofactors UFD1-NPL4 (p97-UN), 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. Here, we screen cofactors and identify FAF2 to potently enhance substrate unfolding by p97-UN. 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, thereby stabilizing and supporting the unfolding of the initiator ubiquitin in a UFD1-dependent manner. We leverage the features of the FAF2 activation motif 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.

PMID:
42603836
Bibliographic data and abstract were imported from PubMed on 16 Aug 2026.

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