{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:26:53Z","timestamp":1787682413601,"version":"build-2784847793"},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100010583","name":"Universit\u00e4t Konstanz","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010583","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The ubiquitin ligase E6AP, encoded by the\n                    <jats:italic>UBE3A<\/jats:italic>\n                    gene, plays a prominent role in human papillomavirus (HPV)-induced cancers. In complex with the HPV E6 oncoprotein, it targets inter alia the tumor suppressor p53 for degradation, thereby contributing to cellular transformation. Besides affecting the substrate spectrum of E6AP, E6 acts as a potent activator of the catalytic activity of E6AP. Here we report that RhoA and its subfamily members RhoB and RhoC serve as substrates of the E6-E6AP complex, but more strikingly, also act as strong inhibitors of the complex. We show that RhoA subfamily members potently inhibit E6-E6AP-mediated ubiquitination and degradation of p53 and that this inhibitory effect is not due to simple substrate competition. In addition to establishing RhoA subfamily members as the first known cellular regulators of the E6-E6AP complex, we provide evidence that RhoA binds to E6AP in the absence of E6. Notably, loss of functional E6AP is the cause of Angelman syndrome (AS), a neurodevelopmental disorder, and RhoA plays a critical role in maintaining synaptic structure and function. Thus, we propose that the interaction of RhoA subfamily members with E6AP is of significance for the development of both HPV-induced cancers and AS.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-67837-8","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:56:31Z","timestamp":1787673391000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Members of the RhoA subfamily of GTPases suppress the stimulatory effect of the HPV E6 oncoprotein on the ubiquitin ligase E6AP"],"prefix":"10.1038","volume":"16","author":[{"given":"Daniela","family":"Eichbichler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Eulich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Stengel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Scheffner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"67837_CR1","first-page":"775","volume":"13","author":"JM Huibregtse","year":"1993","unstructured":"Huibregtse, J. M., Scheffner, M. & Howley, P. M. Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol. Cell. Biol. 13, 775\u2013784 (1993).","journal-title":"Mol. Cell. Biol."},{"key":"67837_CR2","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1038\/nrc798","volume":"2","author":"H zur Hausen","year":"2002","unstructured":"zur Hausen, H. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev. Cancer 2, 342\u2013350 (2002).","journal-title":"Nat. Rev. Cancer"},{"key":"67837_CR3","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41571-022-00603-7","volume":"19","author":"M Lechner","year":"2022","unstructured":"Lechner, M., Liu, J., Masterson, L. & Fenton, T. R. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat. Rev. Clin. Oncol. 19, 306\u2013327 (2022).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"67837_CR4","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.3390\/cancers12082108","volume":"12","author":"A Owais","year":"2020","unstructured":"Owais, A., Mishra, R. K. & Kiyokawa, H. The HECT E3 ligase E6AP\/UBE3A as a therapeutic target in cancer and neurological disorders. Cancers (Basel) 12, 2108 (2020).","journal-title":"Cancers (Basel)"},{"key":"67837_CR5","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/ng0197-70","volume":"15","author":"T Kishino","year":"1997","unstructured":"Kishino, T., Lalande, M. & Wagstaff, J. UBE3A\/E6-AP mutations cause Angelman syndrome. Nat. Genet. 15, 70\u201373 (1997).","journal-title":"Nat. Genet."},{"key":"67837_CR6","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/ng0197-74","volume":"15","author":"T Matsuura","year":"1997","unstructured":"Matsuura, T. et al. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat. Genet. 15, 74\u201377 (1997).","journal-title":"Nat. Genet."},{"key":"67837_CR7","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1159\/000328837","volume":"2","author":"A Dagli","year":"2012","unstructured":"Dagli, A., Buiting, K. & Williams, C. A. Molecular and clinical aspects of Angelman syndrome. Mol. Syndromol. 2, 100\u2013112 (2012).","journal-title":"Mol. Syndromol"},{"key":"67837_CR8","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/nrneurol.2016.133","volume":"12","author":"K Buiting","year":"2016","unstructured":"Buiting, K., Williams, C. & Horsthemke, B. Angelman syndrome - insights into a rare neurogenetic disorder. Nat. Rev. Neurol. 12, 584\u2013593 (2016).","journal-title":"Nat. Rev. Neurol."},{"key":"67837_CR9","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1101\/gr.7.4.368","volume":"7","author":"JS Sutcliffe","year":"1997","unstructured":"Sutcliffe, J. S. et al. The E6-AP ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res. 7, 368\u2013377 (1997).","journal-title":"Genome Res."},{"key":"67837_CR10","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1006\/geno.1997.4617","volume":"41","author":"Y Yamamoto","year":"1997","unstructured":"Yamamoto, Y., Huibregtse, J. M. & Howley, P. M. The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing. Genomics 41, 263\u2013266 (1997).","journal-title":"Genomics"},{"key":"67837_CR11","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/nature07953","volume":"459","author":"JT Glessner","year":"2009","unstructured":"Glessner, J. T. et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569\u2013573 (2009).","journal-title":"Nature"},{"key":"67837_CR12","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.nbd.2008.08.011","volume":"38","author":"A Hogart","year":"2010","unstructured":"Hogart, A., Wu, D., LaSalle, J. M. & Schanen, N. C. The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiol. Dis. 38, 181\u2013191 (2010).","journal-title":"Neurobiol. Dis."},{"key":"67837_CR13","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.2217\/epi.15.70","volume":"7","author":"JM LaSalle","year":"2015","unstructured":"LaSalle, J. M., Reiter, L. T. & Chamberlain, S. J. Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders. Epigenomics 7, 1213\u20131228 (2015).","journal-title":"Epigenomics"},{"key":"67837_CR14","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3389\/fnmol.2019.00109","volume":"12","author":"N Khatri","year":"2019","unstructured":"Khatri, N. & Man, H. Y. The autism and Angelman syndrome protein Ube3A\/E6AP: the gene, E3 ligase ubiquitination targets and neurobiological functions. Front. Mol. Neurosci. 12, 109 (2019).","journal-title":"Front. Mol. Neurosci."},{"key":"67837_CR15","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.virol.2012.09.046","volume":"435","author":"EA White","year":"2013","unstructured":"White, E. A. & Howley, P. M. Proteomic approaches to the study of papillomavirus-host interactions. Virology 435, 57\u201369 (2013).","journal-title":"Virology"},{"key":"67837_CR16","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1146\/annurev-virology-100114-055021","volume":"2","author":"NA Wallace","year":"2015","unstructured":"Wallace, N. A. & Galloway, D. A. Novel functions of the human papillomavirus E6 oncoproteins. Annu. Rev. Virol. 2, 403\u2013423 (2015).","journal-title":"Annu. Rev. Virol."},{"key":"67837_CR17","doi-asserted-by":"publisher","first-page":"18785","DOI":"10.1074\/jbc.274.26.18785","volume":"274","author":"S Kumar","year":"1999","unstructured":"Kumar, S., Talis, A. L. & Howley, P. M. Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J. Biol. Chem. 274, 18785\u201318792 (1999).","journal-title":"J. Biol. Chem."},{"key":"67837_CR18","doi-asserted-by":"publisher","first-page":"6788","DOI":"10.1073\/pnas.1003108107","volume":"107","author":"D Zaaroor-Regev","year":"2010","unstructured":"Zaaroor-Regev, D. et al. Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome. Proc. Natl. Acad. Sci. U S A 107, 6788\u20136793 (2010).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"67837_CR19","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cell.2010.09.038","volume":"143","author":"SS Margolis","year":"2010","unstructured":"Margolis, S. S. et al. EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell 143, 442\u2013455 (2010).","journal-title":"Cell"},{"key":"67837_CR20","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1126\/science.aav5386","volume":"366","author":"AX Sun","year":"2019","unstructured":"Sun, A. X. et al. Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science 366, 1486\u20131492 (2019).","journal-title":"Science"},{"key":"67837_CR21","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1038\/s41467-017-01974-7","volume":"8","author":"Y Wang","year":"2017","unstructured":"Wang, Y. et al. Identifying the ubiquitination targets of E6AP by orthogonal ubiquitin transfer. Nat. Commun. 8, 2232 (2017).","journal-title":"Nat. Commun."},{"key":"67837_CR22","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1038\/s41380-022-01484-z","volume":"27","author":"NJ Pandya","year":"2022","unstructured":"Pandya, N. J. et al. A cross-species spatiotemporal proteomic analysis identifies UBE3A-dependent signaling pathways and targets. Mol. Psychiatry 27, 2590\u20132601 (2022).","journal-title":"Mol. Psychiatry"},{"key":"67837_CR23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/ng0997-14","volume":"17","author":"C Rougeulle","year":"1997","unstructured":"Rougeulle, C., Glatt, H. & Lalande, M. The Angelman syndrome candidate gene, UBE3A\/E6-AP, is imprinted in brain. Nat. Genet. 17, 14\u201315 (1997).","journal-title":"Nat. Genet."},{"key":"67837_CR24","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.1093\/hmg\/10.23.2687","volume":"10","author":"M Runte","year":"2001","unstructured":"Runte, M. et al. The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Mol. Genet. 10, 2687\u20132700 (2001).","journal-title":"Hum. Mol. Genet."},{"key":"67837_CR25","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.1073\/pnas.1815279116","volume":"116","author":"JS Hsiao","year":"2019","unstructured":"Hsiao, J. S. et al. A bipartite boundary element restricts UBE3A imprinting to mature neurons. Proc. Natl. Acad. Sci. U S A 116, 2181\u20132186 (2019).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"67837_CR26","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1038\/s41593-019-0425-0","volume":"22","author":"R Avagliano Trezza","year":"2019","unstructured":"Avagliano Trezza, R. et al. Loss of nuclear UBE3A causes electrophysiological and behavioral deficits in mice and is associated with Angelman syndrome. Nat. Neurosci. 22, 1235\u20131247 (2019).","journal-title":"Nat. Neurosci."},{"key":"67837_CR27","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.cell.2015.06.045","volume":"162","author":"JJ Yi","year":"2015","unstructured":"Yi, J. J. et al. An autism-linked mutation disables phosphorylation control of UBE3A. Cell 162, 795\u2013807 (2015).","journal-title":"Cell"},{"key":"67837_CR28","doi-asserted-by":"publisher","first-page":"9872","DOI":"10.1073\/pnas.1505923112","volume":"112","author":"F Mortensen","year":"2015","unstructured":"Mortensen, F. et al. Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination. Proc. Natl. Acad. Sci. U S A 112, 9872\u20139877 (2015).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"67837_CR29","doi-asserted-by":"publisher","first-page":"19410","DOI":"10.1074\/jbc.M110.205211","volume":"286","author":"S K\u00fchnle","year":"2011","unstructured":"K\u00fchnle, S. et al. Physical and functional interaction of the HECT ubiquitin-protein ligases E6AP and HERC2. J. Biol. Chem. 286, 19410\u201319416 (2011).","journal-title":"J. Biol. Chem."},{"key":"67837_CR30","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1136\/jmedgenet-2012-101367","volume":"50","author":"GV Harlalka","year":"2013","unstructured":"Harlalka, G. V. et al. Mutation of HERC2 causes developmental delay with Angelman-like features. J. Med. Genet. 50, 65\u201373 (2013).","journal-title":"J. Med. Genet."},{"key":"67837_CR31","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.1016\/j.chembiol.2020.08.017","volume":"27","author":"F Offensperger","year":"2020","unstructured":"Offensperger, F. et al. Identification of small-molecule activators of the ubiquitin ligase E6AP\/UBE3A and Angelman Syndrome-derived E6AP\/UBE3A variants. Cell. Chem. Biol. 27, 1510\u20131520 (2020).","journal-title":"Cell. Chem. Biol."},{"key":"67837_CR32","doi-asserted-by":"publisher","first-page":"e202400184","DOI":"10.1002\/cbic.202400184","volume":"25","author":"F M\u00fcller","year":"2024","unstructured":"M\u00fcller, F. et al. Cobalamins function as allosteric activators of an Angelman Syndrome-associated UBE3A\/E6AP variant. Chembiochem 25, e202400184 (2024).","journal-title":"Chembiochem"},{"key":"67837_CR33","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1038\/s41467-024-45920-w","volume":"15","author":"JCK Wang","year":"2024","unstructured":"Wang, J. C. K. et al. Structure of the p53 degradation complex from HPV16. Nat. Commun. 15, 1842 (2024).","journal-title":"Nat. Commun."},{"key":"67837_CR34","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1038\/s41467-024-47586-w","volume":"15","author":"Z Wang","year":"2024","unstructured":"Wang, Z. et al. Structural insights into the functional mechanism of the ubiquitin ligase E6AP. Nat. Commun. 15, 3531 (2024).","journal-title":"Nat. Commun."},{"key":"67837_CR35","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1016\/j.str.2024.12.013","volume":"33","author":"S Kenny","year":"2025","unstructured":"Kenny, S. et al. Structure of E6AP in complex with HPV16-E6 and p53 reveals a novel ordered domain important for E3 ligase activation. Structure 33, 504\u2013516 (2025).","journal-title":"Structure"},{"key":"67837_CR36","doi-asserted-by":"publisher","first-page":"15070","DOI":"10.1074\/jbc.RA120.015603","volume":"295","author":"FA Ebner","year":"2020","unstructured":"Ebner, F. A. et al. A ubiquitin variant-based affinity approach selectively identifies substrates of the ubiquitin ligase E6AP in complex with HPV-11 E6 or HPV-16 E6. J. Biol. Chem. 295, 15070\u201315082 (2020).","journal-title":"J. Biol. Chem."},{"key":"67837_CR37","doi-asserted-by":"publisher","first-page":"7420","DOI":"10.1021\/bi300758e","volume":"51","author":"EC Lessey","year":"2012","unstructured":"Lessey, E. C., Guilluy, C. & Burridge, K. From mechanical force to RhoA activation. Biochemistry 51, 7420\u20137432 (2012).","journal-title":"Biochemistry"},{"key":"67837_CR38","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/0092-8674(92)90163-7","volume":"70","author":"AJ Ridley","year":"1992","unstructured":"Ridley, A. J. & Hall, A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70, 389\u2013399 (1992).","journal-title":"Cell"},{"issue":"5","key":"67837_CR39","doi-asserted-by":"publisher","first-page":"F55","DOI":"10.1016\/j.vaccine.2012.06.083","volume":"30 Suppl","author":"J Doorbar","year":"2012","unstructured":"Doorbar, J. et al. The biology and life-cycle of human papillomaviruses. Vaccine 30 Suppl (5), F55\u201370 (2012).","journal-title":"Vaccine"},{"key":"67837_CR40","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.mrrev.2016.07.002","volume":"772","author":"ME Harden","year":"2017","unstructured":"Harden, M. E. & Munger, K. Human papillomavirus molecular biology. Mutat. Res. Rev. Mutat. Res. 772, 3\u201312 (2017).","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"67837_CR41","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s13229-019-0293-1","volume":"10","author":"I Tonazzini","year":"2019","unstructured":"Tonazzini, I. et al. The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons. Mol. Autism 10, 41 (2019).","journal-title":"Mol. Autism"},{"key":"67837_CR42","doi-asserted-by":"publisher","first-page":"025708","DOI":"10.1088\/1361-6528\/abbb03","volume":"32","author":"R Mezzena","year":"2021","unstructured":"Mezzena, R. et al. Study of adhesion and migration dynamics in ubiquitin E3A ligase (UBE3A)-silenced SYSH5Y neuroblastoma cells by micro-structured surfaces. Nanotechnology 32, 025708 (2021).","journal-title":"Nanotechnology"},{"key":"67837_CR43","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1046\/j.1432-1327.1998.2540643.x","volume":"254","author":"U Nuber","year":"1998","unstructured":"Nuber, U., Schwarz, S. E. & Scheffner, M. The ubiquitin-protein ligase E6-associated protein (E6-AP) serves as its own substrate. Eur. J. Biochem. 254, 643\u2013649 (1998).","journal-title":"Eur. J. Biochem."},{"key":"67837_CR44","doi-asserted-by":"publisher","first-page":"6408","DOI":"10.1128\/JVI.74.14.6408-6417.2000","volume":"74","author":"WH Kao","year":"2000","unstructured":"Kao, W. H., Beaudenon, S. L., Talis, A. L., Huibregtse, J. M. & Howley, P. M. Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase. J. Virol. 74, 6408\u20136417 (2000).","journal-title":"J. Virol."},{"key":"67837_CR45","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/0092-8674(93)90384-3","volume":"75","author":"M Scheffner","year":"1993","unstructured":"Scheffner, M., Huibregtse, J. M., Vierstra, R. D. & Howley, P. M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75, 495\u2013505 (1993).","journal-title":"Cell"},{"key":"67837_CR46","doi-asserted-by":"publisher","first-page":"e1007575","DOI":"10.1371\/journal.ppat.1007575","volume":"15","author":"CM Drews","year":"2019","unstructured":"Drews, C. M., Case, S. & Vande Pol, S. B. E6 proteins from high-risk HPV, low-risk HPV, and animal papillomaviruses activate the Wnt\/beta-catenin pathway through E6AP-dependent degradation of NHERF1. PLoS Pathog. 15, e1007575 (2019).","journal-title":"PLoS Pathog"},{"key":"67837_CR47","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1093\/molbev\/msl145","volume":"24","author":"A Boureux","year":"2007","unstructured":"Boureux, A., Vignal, E., Faure, S. & Fort, P. Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol. Biol. Evol. 24, 203\u2013216 (2007).","journal-title":"Mol. Biol. Evol."},{"key":"67837_CR48","doi-asserted-by":"publisher","first-page":"6","DOI":"10.4161\/21541248.2014.968004","volume":"5","author":"A Schaefer","year":"2014","unstructured":"Schaefer, A., Reinhard, N. R. & Hordijk, P. L. Toward understanding RhoGTPase specificity: structure, function and local activation. Small GTPases 5, 6 (2014).","journal-title":"Small GTPases"},{"key":"67837_CR49","doi-asserted-by":"publisher","first-page":"9656","DOI":"10.1074\/jbc.273.16.9656","volume":"273","author":"K Ihara","year":"1998","unstructured":"Ihara, K. et al. Crystal structure of human RhoA in a dominantly active form complexed with a GTP analogue. J. Biol. Chem. 273, 9656\u20139666 (1998).","journal-title":"J. Biol. Chem."},{"key":"67837_CR50","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/nature16481","volume":"529","author":"D Martinez-Zapien","year":"2016","unstructured":"Martinez-Zapien, D. et al. Structure of the E6\/E6AP\/p53 complex required for HPV-mediated degradation of p53. Nature 529, 541\u2013545 (2016).","journal-title":"Nature"},{"key":"67837_CR51","doi-asserted-by":"publisher","first-page":"4441","DOI":"10.1038\/s41467-018-06953-0","volume":"9","author":"C Sailer","year":"2018","unstructured":"Sailer, C. et al. Structural dynamics of the E6AP\/UBE3A-E6-p53 enzyme-substrate complex. Nat. Commun. 9, 4441 (2018).","journal-title":"Nat. Commun."},{"key":"67837_CR52","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1038\/nbt.2999","volume":"32","author":"Y Feng","year":"2014","unstructured":"Feng, Y. et al. Global analysis of protein structural changes in complex proteomes. Nat. Biotechnol. 32, 1036\u20131044 (2014).","journal-title":"Nat. Biotechnol."},{"key":"67837_CR53","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.cell.2020.12.021","volume":"184","author":"V Cappelletti","year":"2021","unstructured":"Cappelletti, V. et al. Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ. Cell 184, 545\u2013559 (2021).","journal-title":"Cell"},{"key":"67837_CR54","first-page":"4918","volume":"13","author":"JM Huibregtse","year":"1993","unstructured":"Huibregtse, J. M., Scheffner, M. & Howley, P. M. Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol. Cell. Biol. 13, 4918\u20134927 (1993).","journal-title":"Mol. Cell. Biol."},{"key":"67837_CR55","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/314111a0","volume":"314","author":"E Schwarz","year":"1985","unstructured":"Schwarz, E. et al. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 314, 111\u2013114 (1985).","journal-title":"Nature"},{"key":"67837_CR56","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1128\/jvi.61.4.962-971.1987","volume":"61","author":"CC Baker","year":"1987","unstructured":"Baker, C. C. et al. Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines. J. Virol. 61, 962\u2013971 (1987).","journal-title":"J. Virol."},{"key":"67837_CR57","first-page":"2159","volume":"8","author":"JY Chen","year":"1993","unstructured":"Chen, J. Y., Funk, W. D., Wright, W. E., Shay, J. W. & Minna, J. D. Heterogeneity of transcriptional activity of mutant p53 proteins and p53 DNA target sequences. Oncogene 8, 2159\u20132166 (1993).","journal-title":"Oncogene"},{"key":"67837_CR58","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1074\/jbc.M605117200","volume":"282","author":"P Kuballa","year":"2007","unstructured":"Kuballa, P., Matentzoglu, K. & Scheffner, M. The role of the ubiquitin ligase E6-AP in human papillomavirus E6-mediated degradation of PDZ domain-containing proteins. J. Biol. Chem. 282, 65\u201371 (2007).","journal-title":"J. Biol. Chem."},{"issue":"Suppl. 1","key":"67837_CR59","doi-asserted-by":"publisher","first-page":"S4","DOI":"10.1186\/1471-2091-9-S1-S4","volume":"9","author":"S Beaudenon","year":"2008","unstructured":"Beaudenon, S. & Huibregtse, J. M. HPV E6, E6AP and cervical cancer. BMC Biochem. 9 (Suppl. 1), S4 (2008).","journal-title":"BMC Biochem."},{"key":"67837_CR60","doi-asserted-by":"publisher","first-page":"5064","DOI":"10.1158\/0008-5472.CAN-09-3307","volume":"70","author":"A Shai","year":"2010","unstructured":"Shai, A., Pitot, H. C. & Lambert, P. F. E6-associated protein is required for human papillomavirus type 16 E6 to cause cervical cancer in mice. Cancer Res. 70, 5064\u20135073 (2010).","journal-title":"Cancer Res."},{"key":"67837_CR61","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1083\/jcb.119.3.617","volume":"119","author":"P Adamson","year":"1992","unstructured":"Adamson, P., Paterson, H. F. & Hall, A. Intracellular localization of the p21rho proteins. J. Cell. Biol. 119, 617\u2013627 (1992).","journal-title":"J. Cell. Biol."},{"key":"67837_CR62","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1093\/hmg\/ddaf044","volume":"34","author":"ACM van Esbroeck","year":"2025","unstructured":"van Esbroeck, A. C. M. et al. Localization of human UBE3A isoform 3 is highly sensitive to amino acid substitutions at p.Met21 position. Hum. Mol. Genet. 34, 1009\u20131016 (2025).","journal-title":"Hum. Mol. Genet."},{"key":"67837_CR63","doi-asserted-by":"publisher","first-page":"106912","DOI":"10.1016\/j.nbd.2025.106912","volume":"210","author":"PK Gupta","year":"2025","unstructured":"Gupta, P. K., Feuermann, Y. & Kaphzan, H. Dynamic shift in localization of UBE3A across developmental stages in an Angelman syndrome mouse model. Neurobiol. Dis. 210, 106912 (2025).","journal-title":"Neurobiol. Dis."},{"key":"67837_CR64","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1006\/viro.2001.1290","volume":"293","author":"E Guccione","year":"2002","unstructured":"Guccione, E., Massimi, P., Bernat, A. & Banks, L. Comparative analysis of the intracellular location of the high- and low-risk human papillomavirus oncoproteins. Virology 293, 20\u201325 (2002).","journal-title":"Virology"},{"key":"67837_CR65","doi-asserted-by":"publisher","first-page":"6381","DOI":"10.1002\/jcp.26487","volume":"233","author":"JG Kim","year":"2018","unstructured":"Kim, J. G. et al. Regulation of RhoA GTPase and various transcription factors in the RhoA pathway. J. Cell. Physiol. 233, 6381\u20136392 (2018).","journal-title":"J. Cell. Physiol."},{"key":"67837_CR66","doi-asserted-by":"publisher","first-page":"e17380","DOI":"10.1371\/journal.pone.0017380","volume":"6","author":"AD Dubash","year":"2011","unstructured":"Dubash, A. D. et al. The small GTPase RhoA localizes to the nucleus and is activated by Net1 and DNA damage signals. PLoS One 6, e17380 (2011).","journal-title":"PLoS One"},{"key":"67837_CR67","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1126\/science.1090772","volume":"302","author":"HR Wang","year":"2003","unstructured":"Wang, H. R. et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 302, 1775\u20131779 (2003).","journal-title":"Science"},{"key":"67837_CR68","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1080\/21541248.2016.1232583","volume":"7","author":"RB Haga","year":"2016","unstructured":"Haga, R. B. & Ridley, A. J. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases 7, 207\u2013221 (2016).","journal-title":"Small GTPases"},{"key":"67837_CR69","doi-asserted-by":"crossref","unstructured":"Ju, J. A. & Gilkes, D. M. RhoB: team oncogene or team tumor suppressor? Genes (Basel) 2018, 9 (2018).","DOI":"10.3390\/genes9020067"},{"key":"67837_CR70","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1056\/NEJMoa021641","volume":"348","author":"N Munoz","year":"2003","unstructured":"Munoz, N. et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl. J. Med. 348, 518\u2013527 (2003).","journal-title":"N Engl. J. Med."},{"key":"67837_CR71","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.jmb.2005.03.071","volume":"349","author":"K Zanier","year":"2005","unstructured":"Zanier, K. et al. Kinetic analysis of the interactions of human papillomavirus E6 oncoproteins with the ubiquitin ligase E6AP using surface plasmon resonance. J. Mol. Biol. 349, 401\u2013412 (2005).","journal-title":"J. Mol. Biol."},{"key":"67837_CR72","doi-asserted-by":"publisher","first-page":"19414","DOI":"10.1038\/s41598-021-97898-w","volume":"11","author":"GL Sell","year":"2021","unstructured":"Sell, G. L. et al. Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice. Sci. Rep. 11, 19414 (2021).","journal-title":"Sci. Rep."},{"key":"67837_CR73","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1128\/MCB.01372-06","volume":"27","author":"FC Morales","year":"2007","unstructured":"Morales, F. C. et al. NHERF1\/EBP50 head-to-tail intramolecular interaction masks association with PDZ domain ligands. Mol. Cell. Biol. 27, 2527\u20132537 (2007).","journal-title":"Mol. Cell. Biol."},{"key":"67837_CR74","doi-asserted-by":"publisher","first-page":"4129","DOI":"10.1002\/j.1460-2075.1991.tb04990.x","volume":"10","author":"JM Huibregtse","year":"1991","unstructured":"Huibregtse, J. M., Scheffner, M. & Howley, P. M. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 10, 4129\u20134135 (1991).","journal-title":"EMBO J."},{"key":"67837_CR75","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1007\/s10529-017-2330-5","volume":"39","author":"Q Liang","year":"2017","unstructured":"Liang, Q., Huang, Z., Zhang, Y. & Li, H. Immobilization of Ulp1 protease on NHS-activated Sepharose: a useful tool for cleavage of the SUMO tag of recombinant proteins. Biotechnol. Lett. 39, 1025\u20131031 (2017).","journal-title":"Biotechnol. Lett."},{"key":"67837_CR76","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.ab.2011.06.034","volume":"418","author":"CE Berndsen","year":"2011","unstructured":"Berndsen, C. E. & Wolberger, C. A spectrophotometric assay for conjugation of ubiquitin and ubiquitin-like proteins. Anal. Biochem. 418, 102\u2013110 (2011).","journal-title":"Anal. Biochem."},{"key":"67837_CR77","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/978-1-60761-913-0_15","volume":"681","author":"M Lebendiker","year":"2011","unstructured":"Lebendiker, M. & Danieli, T. Purification of proteins fused to maltose-binding protein. Methods Mol. Biol. 681, 281\u2013293 (2011).","journal-title":"Methods Mol. Biol."},{"key":"67837_CR78","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/nprot.2013.168","volume":"9","author":"A Leitner","year":"2014","unstructured":"Leitner, A., Walzthoeni, T. & Aebersold, R. Lysine-specific chemical cross-linking of protein complexes and identification of cross-linking sites using LC-MS\/MS and the xQuest\/xProphet software pipeline. Nat. Protoc. 9, 120\u2013137 (2014).","journal-title":"Nat. Protoc."},{"key":"67837_CR79","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s13361-014-1001-1","volume":"26","author":"M G\u00f6tze","year":"2015","unstructured":"G\u00f6tze, M. et al. Automated assignment of MS\/MS cleavable cross-links in protein 3D-structure analysis. J. Am. Soc. Mass. Spectrom. 26, 83\u201397 (2015).","journal-title":"J. Am. Soc. Mass. Spectrom."},{"key":"67837_CR80","doi-asserted-by":"publisher","first-page":"2805","DOI":"10.1021\/acs.analchem.7b04915","volume":"90","author":"C Iacobucci","year":"2018","unstructured":"Iacobucci, C. et al. Carboxyl-photo-reactive MS-cleavable cross-linkers: unveiling a hidden aspect of diazirine-based reagents. Anal. Chem. 90, 2805\u20132809 (2018).","journal-title":"Anal. Chem."},{"key":"67837_CR81","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/s41596-022-00771-x","volume":"18","author":"L Malinovska","year":"2023","unstructured":"Malinovska, L. et al. Proteome-wide structural changes measured with limited proteolysis-mass spectrometry: an advanced protocol for high-throughput applications. Nat. Protoc. 18, 659\u2013682 (2023).","journal-title":"Nat. Protoc."},{"key":"67837_CR82","doi-asserted-by":"publisher","first-page":"2296","DOI":"10.1074\/mcp.RA117.000314","volume":"16","author":"R Bruderer","year":"2017","unstructured":"Bruderer, R. et al. Optimization of experimental parameters in data-independent mass spectrometry significantly increases depth and reproducibility of results. Mol. Cell. Proteom. 16, 2296\u20132309 (2017).","journal-title":"Mol. Cell. Proteom."},{"key":"67837_CR83","doi-asserted-by":"publisher","first-page":"e2100103","DOI":"10.1002\/pmic.202100103","volume":"22","author":"JP Schessner","year":"2022","unstructured":"Schessner, J. P., Voytik, E. & Bludau, I. A practical guide to interpreting and generating bottom-up proteomics data visualizations. Proteomics 22, e2100103 (2022).","journal-title":"Proteomics"},{"key":"67837_CR84","doi-asserted-by":"publisher","first-page":"D543","DOI":"10.1093\/nar\/gkae1011","volume":"53","author":"Y Perez-Riverol","year":"2025","unstructured":"Perez-Riverol, Y. et al. The PRIDE database at 20 years: 2025 update. Nucleic Acids Res. 53, D543\u2013D553 (2025).","journal-title":"Nucleic Acids Res."},{"key":"67837_CR85","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.virol.2009.07.029","volume":"393","author":"V Tomaic","year":"2009","unstructured":"Tomaic, V., Pim, D. & Banks, L. The stability of the human papillomavirus E6 oncoprotein is E6AP dependent. Virology 393, 7\u201310 (2009).","journal-title":"Virology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-67837-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-67837-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-67837-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:03:53Z","timestamp":1787681033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-67837-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":85,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["67837"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-67837-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]},"assertion":[{"value":"7 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"26683"}}