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The DUB Cezanne-1 catalyzes the cleavage of the iso-peptide bond of Lys11-linked polyubiquitin chains with high selectivity. Crystal structures of Cezanne-1 in different states provide important insight regarding the complex formation and global changes during the catalytic cycle but are lacking details of dynamics and control of activation. Activity-based probes are used to isolate intermediate states upon forming covalent bonds with the DUB active site. Those, however, may lead to structures that are non-native. Conformational changes of Cezanne-1, during its process of activation and proteolytic activity, are investigated using all-atom molecular dynamics (MD) simulations of the ubiquitin-free, diubiquitin-bound, and monoubiquitin-bound Cezanne-1 DUB for a total of \u223c18 \u03bcs. Our results show that ubiquitin-free Cezanne-1 dynamically shuttles between catalytically competent and incompetent states which suggests that its activation is independent of substrate binding. The catalytically competent substrate-free Cezanne-1 promotes distal ubiquitin substrate access to the catalytic center. The subsequent binding of the proximal ubiquitin shifts the equilibrium toward the catalytically competent state of the dyad, thereby promoting proteolysis of the iso-peptide bond. After cleavage of the scissile bond, sequential dissociation of first the proximal ubiquitin induces the inactivation of Cezanne-1. The subsequent release of the distal ubiquitin fully reconstitutes the inactive substrate-free state of Cezanne-1. The process of activation and catalytic turnover of DUB Cezanne-1 is a multistage cycle with several critical dynamic transitions that cannot be characterized based on protein structures alone. Activity-based probes of cysteine proteases lead to non-native protein\u2013protein contacts, which need to be resolved in order to be able to issue statements about physiological states and substrate binding.<\/jats:p>","DOI":"10.1021\/acs.jcim.2c01281","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T11:46:14Z","timestamp":1679399174000},"page":"2084-2094","source":"Crossref","is-referenced-by-count":2,"title":["Structural Dynamics\nof Lys11-Selective Deubiquitinylase\nCezanne\u20111 during the Catalytic Cycle"],"prefix":"10.1021","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3579-4552","authenticated-orcid":true,"given":"Metehan","family":"Ilter","sequence":"first","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems , , ,","place":["Magdeburg, Germany, 39106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Schulze-Niemand","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems , , ,","place":["Magdeburg, Germany, 39106"]},{"name":"Otto von Guericke University , , ,","place":["Magdeburg, Germany, 39120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Naumann","sequence":"additional","affiliation":[{"name":"Otto von Guericke University , , ,","place":["Magdeburg, Germany, 39120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7793-0052","authenticated-orcid":true,"given":"Matthias","family":"Stein","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems , , ,","place":["Magdeburg, Germany, 39106"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"2026081804433210500_cit1","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/cr.2016.39","article-title":"Ubiquitin Modifications","volume":"26","author":"Swatek","year":"2016","journal-title":"Cell\nRes."},{"key":"2026081804433210500_cit2","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The Ubiquitin Code","volume":"81","author":"Komander","year":"2012","journal-title":"Annu. 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Sci."},{"key":"2026081804433210500_cit5","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1042\/EBC20210042","article-title":"Ubiquitination\nof the Ubiquitin-Binding Machinery: How Early ESCRT Components Are\nControlled","volume":"66","author":"Korbei","year":"2022","journal-title":"Essays Biochem"},{"key":"2026081804433210500_cit6","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/s41580-021-00448-5","article-title":"Ubiquitin\nLigases: Guardians of Mammalian Development","volume":"23","author":"Cruz\nWalma","year":"2022","journal-title":"Nat. Rev. Mol. Cell Bio."},{"key":"2026081804433210500_cit7","doi-asserted-by":"publisher","first-page":"102198","DOI":"10.1016\/j.jbc.2022.102198","article-title":"Mechanisms Orchestrating\nthe Enzymatic Activity and\nCellular Functions of Deubiquitinases","volume":"298","author":"Estavoyer","year":"2022","journal-title":"J. Biol.\nChem."},{"key":"2026081804433210500_cit8","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1042\/BCJ20210735","article-title":"Deubiquitinases\nin Cell Death and Inflammation","volume":"479","author":"Newton","year":"2022","journal-title":"Biochem. J."},{"key":"2026081804433210500_cit9","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s41580-019-0099-1","article-title":"Breaking the Chains: Deubiquitylating\nEnzyme Specificity Begets Function","volume":"20","author":"Clague","year":"2019","journal-title":"Nat. Rev.\nMol. 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Microbiol."},{"key":"2026081804433210500_cit15","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1146\/annurev-biochem-061516-044916","article-title":"Mechanisms of Deubiquitinase\nSpecificity and Regulation","volume":"86","author":"Mevissen","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"2026081804433210500_cit16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms5763","article-title":"Screening\nof DUB Activity and Specificity by MALDI-TOF Mass Spectrometry","volume":"5","author":"Ritorto","year":"2014","journal-title":"Nat. Commun."},{"key":"2026081804433210500_cit17","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1038\/nsmb.1873","article-title":"Lys11-Linked Ubiquitin Chains Adopt\nCompact Conformations and Are Preferentially Hydrolyzed by the Deubiquitinase\nCezanne","volume":"17","author":"Bremm","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026081804433210500_cit18","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/nature19836","article-title":"Molecular\nBasis of Lys11-Polyubiquitin Specificity\nin the Deubiquitinase Cezanne","volume":"538","author":"Mevissen","year":"2016","journal-title":"Nature"},{"key":"2026081804433210500_cit19","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.cell.2008.04.012","article-title":"Mechanism\nof Ubiquitin-Chain Formation by the Human Anaphase-Promoting Complex","volume":"133","author":"Jin","year":"2008","journal-title":"Cell"},{"key":"2026081804433210500_cit20","doi-asserted-by":"publisher","first-page":"18213","DOI":"10.1073\/pnas.0907887106","article-title":"Identification of a Physiological E2Module for the Human Anaphase-Promoting\nComplex","volume":"106","author":"Williamson","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Cancer\nRes."},{"key":"2026081804433210500_cit31","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.cell.2013.05.046","article-title":"OTU Deubiquitinases Reveal Mechanisms of Linkage\nSpecificity and Enable Ubiquitin Chain Restriction Analysis","volume":"154","author":"Mevissen","year":"2013","journal-title":"Cell"},{"key":"2026081804433210500_cit32","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrd.2017.152","article-title":"Deubiquitylating\nEnzymes and Drug Discovery: Emerging Opportunities","volume":"17","author":"Harrigan","year":"2018","journal-title":"Nat. Rev. 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