Structural dynamics of substrate processing by the p97-Ufd1-Npl4-FAF1 machinery
Abstract
The AAA-ATPase VCP/p97 unfolds ubiquitylated proteins in key signaling and cellular homeostasis pathways, yet the mechanisms by which Ufd1-Npl4 and FAF1 adapters handle ubiquitin chains to coordinate substrate loading and processing remain unclear. Our cryo-EM study of p97-Ufd1-Npl4 and FAF1 engaging a substrate reveal interactions that drive substrate processing. While Npl4 is capped by distal ubiquitins, and the initiator ubiquitin can be traced from the Npl4 groove to the ATPase channel at near-atomic resolution, we find that the Npl4 tower adaptively responds to the configurational changes in the ATPase motor’s spiral staircase. A helix in FAF1 together with the Ufd1-UT3 domain engage proximal ubiquitins while providing the necessary structural plasticity to accommodate this motion and deliver ubiquitins to Npl4’s groove. Our study reveals the intricate, dynamic interplay between p97, Ufd1-Npl4, and FAF1 in efficient processing of ubiquitylated substrates.
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BibTeX
@article{drakonaki2026structural,
title = {{Structural dynamics of substrate processing by the p97-Ufd1-Npl4-FAF1 machinery}},
author = {Athina Drakonaki and Johannes van den Boom and Alexander Kröning and Hemmo Meyer and Christos Gatsogiannis},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78639-x},
url = {https://www.nature.com/articles/s41467-026-78639-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Structural dynamics of substrate processing by the p97-Ufd1-Npl4-FAF1 machinery
AU - Athina Drakonaki
AU - Johannes van den Boom
AU - Alexander Kröning
AU - Hemmo Meyer
AU - Christos Gatsogiannis
PY - 2026
DA - 2026/10/25
JO - Nature Communications
DO - 10.1038/s41467-026-78639-x
UR - https://www.nature.com/articles/s41467-026-78639-x
AB - The AAA-ATPase VCP/p97 unfolds ubiquitylated proteins in key signaling and cellular homeostasis pathways, yet the mechanisms by which Ufd1-Npl4 and FAF1 adapters handle ubiquitin chains to coordinate substrate loading and processing remain unclear. Our cryo-EM study of p97-Ufd1-Npl4 and FAF1 engaging a substrate reveal interactions that drive substrate processing. While Npl4 is capped by distal ubiquitins, and the initiator ubiquitin can be traced from the Npl4 groove to the ATPase channel at near-atomic resolution, we find that the Npl4 tower adaptively responds to the configurational changes in the ATPase motor’s spiral staircase. A helix in FAF1 together with the Ufd1-UT3 domain engage proximal ubiquitins while providing the necessary structural plasticity to accommodate this motion and deliver ubiquitins to Npl4’s groove. Our study reveals the intricate, dynamic interplay between p97, Ufd1-Npl4, and FAF1 in efficient processing of ubiquitylated substrates.
SN - 2041-1723
ER -