Ann Schirin Mirsanaye, Saskia Hoffmann, Melanie Weisser, Andreas Mund, Blanca Lopez Mendez, Dimitris Typas, Johannes van den Boom, Bente Benedict, Ivo A Hendriks, Michael Lund Nielsen, Hemmo Meyer, Julien P Duxin, Guillermo Montoya, Niels Mailand
The hexameric AAA+ ATPase p97/VCP functions as an essential mediator of ubiquitin-dependent cellular processes, extracting ubiquitylated proteins from macromolecular complexes or membranes by catalyzing their unfolding. p97 is directed to ubiquitylated client proteins via multiple cofactors, most of which interact with the p97 N-domain. Here, we discover that FAM104A, a protein of unknown function also named VCF1 (VCP/p97 nuclear Cofactor Family member 1), acts as a p97 cofactor in human cells. Detailed structure-function studies reveal that VCF1 directly binds p97 via a conserved α-helical motif that recognizes the p97 N-domain with unusually high affinity, exceeding that of other cofactors...
March 19, 2024: Nature Communications