A non-symmetrical p97 conformation initiates a multistep recruitment of Ufd1/Npl4

Michal Arie, Donna Matzov, Rotem Karmona, Natalia Szenkier, Ariel Stanhill, Ami Navon

Research output: Contribution to journalArticlepeer-review

Abstract

In vitro experiments and cryo-EM structures of p97 and its cofactor, Ufd1/Npl4 (UN), elucidated substrate processing. Yet, the structural transitions and the related ATPase cycle upon UN binding remain unresolved. We captured two discrete conformations: One in which D1 protomers are ATP bound, while the D2 subunits are in the ADP state, presumably required for substrate engagement with the D2 pore; and a heterologous nucleotide state within the D1 ring in which only two NTDs are in the “up” ATP state that favors UN binding. Further analysis suggests that initially, UN binds p97’s non-symmetrical conformation, this association promotes a structural transition upon which five NTDs shift to an “up” state and are poised to bind ATP. The UBXL domain of Npl4 was captured bound to an NTD in the ADP state, demonstrating a conformation that may provide directionality to incoming substrate and introduce the flexibility needed for substrate processing.

Original languageEnglish
Article number110061
JournaliScience
Volume27
Issue number6
DOIs
StatePublished - 21 Jun 2024

Bibliographical note

Publisher Copyright:
© 2024

Keywords

  • Molecular Structure
  • Proteomics
  • Structural Biology

Fingerprint

Dive into the research topics of 'A non-symmetrical p97 conformation initiates a multistep recruitment of Ufd1/Npl4'. Together they form a unique fingerprint.

Cite this