Year: 2026
Type: article
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.
Source: Nature Communications
Institutions: University of Münster, University of Duisburg-Essen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G2760725075, G4955048828, G5990751553, G6894471297, 300kV hochauflösendes KryoElektronenmikroskopie Setup, Biochemische Rekonstitution und Entschlüsselung der p97unterstützten Proteindegradation im Proteasome des Menschen, G7912993671, SFB 1430: Molekulare Mechanismen von Zellzustandsübergängen, G8760597890
OpenAlex ID: W7223573632