Mechanistic insight into substrate processing and allosteric inhibition of human p97

Aboard the ISS: intersubunit signaling revealed in the p97 ATPase

“…1c). The unprecedented asynchronous ATP-hydrolysis states of D1 and D2 in the same subunit observed by Pan et al provide insights into how this may occur 14 . For example, the authors observe ADP in the D1 domain of subunit 4, but ATP in D2.…”

“…The original discovery of p97 and the observation of this structural arrangement was aided by the abundance of p97 in Xenopus laevis oocytes, as negative-stain electron microscopy of p97 purified from this source revealed an oligomer with hexameric radial symmetry 9 . Since these original images, the structurefunction relationship in p97 was analyzed using both X-ray crystallography and cryo-electron microscopy (cryo-EM) [10][11][12][13][14] . Although these works were seminal in the initial understanding of p97, in these structures, p97 was captured in the absence of substrate and showed perfectly symmetric assemblies, reminiscent of the first p97 images.…”

“…In this issue of Nature Structural & Molecular Biology, Pan et al 14 show that the p97 hexamer breaks symmetry and pinches around the unfolded substrate as it is unfolded (Fig. 1b).…”

“…For one, the neighboring ISS must be removed from the ATP-binding pocket for hydrolysis to occur. Based on these structures 14 , cryo-EM studies on Cdc48, the yeast homologue of p97, and the archaeal homologue VAT, ATP hydrolysis is expected to occur sequentially in subunits 5,17,18 . Thus, in the context of the new findings provided by Pan et al, the ISS of subunit 5, for example, must retract from subunit 4 so that hydrolysis and NT exchange can occur in subunit 4 (Fig.…”

“…19 ). The transition from initiation 5 to translocation 14 would probably require dislodging of the p97 cofactor 20 .…”