Structural dynamics of substrate processing by the p97-Ufd1-Npl4-FAF1 machinery.

Cryo-EM reveals that p97-Ufd1-Npl4-FAF1 coordinates ubiquitylated substrate processing by adaptively coupling the Npl4 tower and FAF1/Ufd1 domains to ATPase spiral staircase motion.

• Why it matters: The mechanisms by which Ufd1-Npl4 and FAF1 handle ubiquitin chains to coordinate substrate loading and processing are unclear, limiting understanding of p97’s signaling and homeostasis roles.
• What they did: Using cryo-EM, the study visualized p97-Ufd1-Npl4 and FAF1 engaging a substrate, tracing the initiator ubiquitin from the Npl4 groove to the ATPase channel at near-atomic resolution.
• The result: Npl4 is capped by distal ubiquitins, while a FAF1 helix with the Ufd1-UT3 domain engages proximal ubiquitins, providing structural plasticity to deliver ubiquitins to Npl4’s groove for efficient processing.