{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:12:35Z","timestamp":1778148755414,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,18]]},"group-title":"Molecular Biology","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The multifunctional AAA+ ATPase p97\/VCP is a pivotal regulator of cellular proteostasis, extracting polyubiquitinated substrates from protein complexes or organelle membranes for proteasomal degradation. Mutations in p97 are linked to a broad spectrum of neurodegenerative disorders, including multisystem proteinopathy and amyotrophic lateral sclerosis. Here, we provide insights into the basis of dysfunction in p97\n                  <jats:sup>D395G<\/jats:sup>\n                  , implicated in vacuolar tauopathy, using an integrated structural approach. The mutation destabilizes the interaction network in the transient ADP.P\n                  <jats:sub>i<\/jats:sub>\n                  state previously identified in p97\n                  <jats:sup>WT<\/jats:sup>\n                  and alters the dynamics of the linker between the tandem ATPase domains, resulting in decreased ATPase activity. We further demonstrate that the D395G mutation sensitizes p97 to oxidative stress by enhancing C522 oxidation, thereby perturbing nucleotide binding in D2, and define the functional basis of this oxidative inactivation of p97. These findings reveal redox control as a key regulatory layer of the p97 ATPase cycle and provide a mechanistic framework for how oxidative stress contributes to p97-associated neurodegeneration.\n                <\/jats:p>","DOI":"10.64898\/2026.04.16.718620","type":"posted-content","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T04:00:11Z","timestamp":1776571211000},"source":"Crossref","is-referenced-by-count":0,"title":["The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97\/VCP"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4143-5473","authenticated-orcid":false,"given":"Smruti R.","family":"Rout","sequence":"first","affiliation":[{"name":"Institute for Auditory Neuroscience, University Medical Center G\u00f6ttingen, 37077 G\u00f6ttingen, Germany"},{"name":"Institute for Neuropathology, University Medical Center G\u00f6ttingen, 37073 G\u00f6ttingen, Germany"},{"name":"Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells (MBExC), University of G\u00f6ttingen, 37073 G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-2428","authenticated-orcid":false,"given":"Martin","family":"Kulke","sequence":"additional","affiliation":[{"name":"Center for Functional Protein Assemblies, Technical University of Munich, 85748 Garching, Germany"},{"name":"Department of Physics, Technical University of Munich, 85748 Garching, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5280-2041","authenticated-orcid":false,"given":"Maxim","family":"Droemer","sequence":"additional","affiliation":[{"name":"Faculty for Chemistry and Pharmacy, Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen, 81377 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel","family":"Wendel","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Konstanz, 78457 Konstanz, Germany"},{"name":"Konstanz Research School of Chemical Biology, University of Konstanz, 78457 Konstanz, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2801-3084","authenticated-orcid":false,"given":"Tat Cheung","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute for Neuropathology, University Medical Center G\u00f6ttingen, 37073 G\u00f6ttingen, Germany"},{"name":"Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells (MBExC), University of G\u00f6ttingen, 37073 G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0862-1725","authenticated-orcid":false,"given":"Tristan A.","family":"Mauck","sequence":"additional","affiliation":[{"name":"Center for Functional Protein Assemblies, Technical University of Munich, 85748 Garching, Germany"},{"name":"Department of Physics, Technical University of Munich, 85748 Garching, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Asgari","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Florida State University College of Medicine, 1115 W. 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