Structural insights into the interaction of human p97 N-terminal domain and SHP motif in Derlin-1 rhomboid pseudoprotease

FEBS Lett. 2016 Dec;590(23):4402-4413. doi: 10.1002/1873-3468.12447. Epub 2016 Oct 21.


The interaction of the rhomboid pseudoprotease Derlin-1 and p97 is crucial for the retrotranslocation of polyubiquitinated substrates in the endoplasmic reticulum-associated degradation pathway. We report a 2.25 Å resolution structure of the p97 N-terminal domain (p97N) in complex with the Derlin-1 SHP motif. Remarkably, the SHP motif adopts a short, antiparallel β-strand that interacts with the β-sheet of p97N-a site distinct from that to which most p97 adaptor proteins bind. Mutational and biochemical analyses contributed to defining the specific interaction, demonstrating the importance of a highly conserved binding pocket on p97N and a signature motif on SHP. Our findings may also provide insights into the interactions between other SHP-containing proteins and p97N.

Keywords: Derlin-1; SHP motif; crystal structure; endoplasmic reticulum-associated degradation; p97.

Publication types

  • Letter

MeSH terms

  • Adenosine Triphosphatases / chemistry*
  • Adenosine Triphosphatases / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Apoproteins / chemistry
  • Apoproteins / metabolism
  • Binding Sites
  • Conserved Sequence
  • Endoplasmic Reticulum-Associated Degradation
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism*
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Domains


  • Apoproteins
  • DERL1 protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • Adenosine Triphosphatases
  • p97 ATPase