Direct observation of ATP-driven ubiquitin chain handling by Cdc48

Direct observation of ATP-driven ubiquitin chain handling by Cdc48 | bioRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Direct observation of ATP-driven ubiquitin chain handling by Cdc48 View ORCID Profile D. Choudhary , View ORCID Profile J. R. Tait , View ORCID Profile M. Kracht , A. Roland , View ORCID Profile J. V. D. Boom , V. Sunderlíková , View ORCID Profile H. Meyer , View ORCID Profile S. J. Tans doi: https://doi.org/10.64898/2026.01.30.702746 D. Choudhary 1 Autonomous Matter Department, AMOLF Institute; Amsterdam , the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for D. Choudhary J. R. Tait 1 Autonomous Matter Department, AMOLF Institute; Amsterdam , the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for J. R. Tait M. Kracht 2 Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen; Essen , Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for M. Kracht A. Roland 1 Autonomous Matter Department, AMOLF Institute; Amsterdam , the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site J. V. D. Boom 2 Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen; Essen , Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for J. V. D. Boom V. Sunderlíková 1 Autonomous Matter Department, AMOLF Institute; Amsterdam , the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site H. Meyer 2 Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen; Essen , Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for H. Meyer S. J. Tans 1 Autonomous Matter Department, AMOLF Institute; Amsterdam , the Netherlands 3 Bionanoscience Department, Kavli Institute of Nanoscience Delft, Delft University of Technology; Delft , the Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for S. J. Tans For correspondence: tans{at}amolf.nl Abstract Full Text Info/History Metrics Supplementary material Preview PDF Abstract Cdc48 (p97 or VCP in metazoans) targets polyubiquitin to selectively disassemble and degrade proteins. Cdc48 is believed to move along the ubiquitin chain towards linked proteins, but this has not been directly observed. By following single molecules in time, we find that the polypeptide branch points of ubiquitin chains are repeatedly inserted and rejected from the Cdc48 pore in ATP-driven manner, in bursts lasting up to seconds. This non-processive mode either ends by terminal substrate rejection, or advances to processive action, which drives ubiquitin unfolding in two steps, branch point translocation, and the extrusion of ubiquitin and linked protein as polypeptide loops in trans . Final retrograde movement can bring polypeptide segments back to cis . Our results establish the dynamics of ubiquitin chain handling by Cdc48, reveal key hallmarks of kinetic proofreading. We speculate that Cdc48 translocation may play a role in ubiquitin chain selection. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared Nederlandse Organisatie voor Wetenschappelijk Onderzoek , 024.003.019 European Research Council, https://ror.org/0472cxd90 , 101072047 Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64 , INST-208767513-1 , 509479817 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted February 01, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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