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VCP/p97, an enzyme critical to proteostasis, is regulated through interactions with protein adaptors targeting it to specific cellular tasks. One such adaptor, p47, forms a complex with p97 to direct lipid membrane remodeling. Here, we use NMR and other biophysical methods to study the structural dynamics of p47 and p47-p97 complexes. Disordered regions in p47 are shown to be critical in directing intra-p47 and p47-p97 interactions via a pair of previously unidentified linear motifs. One of these, an SHP domain, regulates p47 binding to p97 in a manner that depends on the nucleotide state of p97. NMR and electron cryomicroscopy data have been used as restraints in molecular dynamics trajectories to develop structural ensembles for p47-p97 complexes in adenosine diphosphate (ADP)- and adenosine triphosphate (ATP)-bound conformations, highlighting differences in interactions in the two states. Our study establishes the importance of intrinsically disordered regions in p47 for the formation of functional p47-p97 complexes.


Alexander E Conicella, Rui Huang, Zev A Ripstein, Ai Nguyen, Eric Wang, Thomas Löhr, Peter Schuck, Michele Vendruscolo, John L Rubinstein, Lewis E Kay. An intrinsically disordered motif regulates the interaction between the p47 adaptor and the p97 AAA+ ATPase. Proceedings of the National Academy of Sciences of the United States of America. 2020 Oct 20;117(42):26226-26236

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PMID: 33028677

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