{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:23:46Z","timestamp":1791685426979,"version":"4.3.4"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS","award":["Ricerca Corrente 2022"],"award-info":[{"award-number":["Ricerca Corrente 2022"]}]},{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS","award":["AARG-21-847593"],"award-info":[{"award-number":["AARG-21-847593"]}]},{"name":"Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS","award":["GR-2016-02363982"],"award-info":[{"award-number":["GR-2016-02363982"]}]},{"name":"Alzheimer\u2019s Association","award":["Ricerca Corrente 2022"],"award-info":[{"award-number":["Ricerca Corrente 2022"]}]},{"name":"Alzheimer\u2019s Association","award":["AARG-21-847593"],"award-info":[{"award-number":["AARG-21-847593"]}]},{"name":"Alzheimer\u2019s Association","award":["GR-2016-02363982"],"award-info":[{"award-number":["GR-2016-02363982"]}]},{"name":"Italian Minister of Health","award":["Ricerca Corrente 2022"],"award-info":[{"award-number":["Ricerca Corrente 2022"]}]},{"name":"Italian Minister of Health","award":["AARG-21-847593"],"award-info":[{"award-number":["AARG-21-847593"]}]},{"name":"Italian Minister of Health","award":["GR-2016-02363982"],"award-info":[{"award-number":["GR-2016-02363982"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A Disintegrin and Metalloprotease 10, also known as ADAM10, is a cell surface protease ubiquitously expressed in mammalian cells where it cuts several membrane proteins implicated in multiple physiological processes. The dysregulation of ADAM10 expression and function has been implicated in pathological conditions, including Alzheimer\u2019s disease (AD). Although it has been suggested that ADAM10 is expressed as a zymogen and the removal of the prodomain results in its activation, other potential mechanisms for the ADAM10 proteolytic function and activation remain unclear. Another suggested mechanism is post-translational modification of the cytoplasmic domain, which regulates ADAM10-dependent protein ectodomain shedding. Therefore, the precise and temporal activation of ADAM10 is highly desirable to reveal the fine details of ADAM10-mediated cleavage mechanisms and protease-dependent therapeutic applications. Here, we present a strategy to control prodomain and cytosolic tail cleavage to regulate ADAM10 shedding activity without the intervention of small endogenous molecule signaling pathways. We generated a series of engineered ADAM10 analogs containing Tobacco Etch Virus protease (TEV) cleavage site (TEVcs), rendering ADAM10 cleavable by TEV. This strategy revealed that, in the absence of other stimuli, the TEV-mediated removal of the prodomain could not activate ADAM10. However, the TEV-mediated cleavage of the cytosolic domain significantly increased ADAM10 activity. Then, we generated ADAM10 with a minimal constitutively catalytic activity that increased significantly in the presence of TEV or after activating a chemically activatable TEV. Our results revealed a bioengineering strategy for controlling the ADAM10 activity in living cells, paving the way to obtain spatiotemporal control of ADAM10. Finally, we proved that our approach of controlling ADAM10 promoted \u03b1-secretase activity and the non-amyloidogenic cleavage of amyloid-\u03b2 precursor protein (APP), thereby increasing the production of the neuroprotective soluble ectodomain (sAPP\u03b1). Our bioengineering strategy has the potential to be exploited as a next-generation gene therapy for AD.<\/jats:p>","DOI":"10.3390\/ijms24020917","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T05:02:30Z","timestamp":1672808550000},"page":"917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Bioengineering Strategy to Control ADAM10 Activity in Living Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0064-1505","authenticated-orcid":false,"given":"Francesco","family":"Pastore","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6988-0040","authenticated-orcid":false,"given":"Martina","family":"Battistoni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimondo","family":"Sollazzo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6986-4390","authenticated-orcid":false,"given":"Pietro","family":"Renna","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8473-8074","authenticated-orcid":false,"given":"Fabiola","family":"Paciello","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica Donatella","family":"Li Puma","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-4251","authenticated-orcid":false,"given":"Eugenio","family":"Barone","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi-Fanelli\u201d, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onur","family":"Dagliyan","sequence":"additional","affiliation":[{"name":"Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5315-0163","authenticated-orcid":false,"given":"Cristian","family":"Ripoli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7253-1685","authenticated-orcid":false,"given":"Claudio","family":"Grassi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E2074","DOI":"10.1073\/pnas.1222387110","article-title":"ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling","volume":"110","author":"Miller","year":"2013","journal-title":"Proc. Natl. Acad. Sci. 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