The type II AAA ATPase p97 interacts with a large number of cofactors that
regulate its function by recruiting it to different cellular pathways. Most of
the cofactors interact with the N-terminal (N) domain of p97, either via
ubiquitin-like domains or short linear binding motifs. While some linear binding
motifs form α helices, another group features short stretches of unstructured
hydrophobic sequences as found in the so-called SHP (BS1, binding segment 1)
motif. Here we present the crystal structure of a SHP-binding motif in complex
with p97, which reveals a so far uncharacterized binding site on the p97 N
domain that is different from the conserved binding surface of all other known
p97 cofactors. This finding explains how cofactors like UFD1/NPL4 and p47 can
utilize a bipartite binding mechanism to interact simultaneously with the same
p97 monomer via their ubiquitin-like domain and SHP motif.
