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PKC with impaired autoinhibition is removed from the cell by quality-control mechanisms to prevent the accumulation of aberrantly active enzyme. Here, we examine how a highly conserved residue in the C1A domain of cPKC isozymes permits quality-control degradation when mutated to histidine in cancer (PKC\u03b2-R42H) and blocks down-regulation when mutated to proline in the neurodegenerative disease spinocerebellar ataxia (PKC\u03b3-R41P). Using FRET-based biosensors, we determined that mutation of R42 to any residue, including lysine, resulted in reduced autoinhibition as indicated by higher basal activity and faster agonist-induced plasma membrane translocation. R42 is predicted to form a stabilizing salt bridge with E655 in the C-tail and mutation of E655, but not neighboring E657, also reduced autoinhibition. Western blot analysis revealed that whereas R42H had reduced stability, the R42P mutant was stable and insensitive to activator-induced ubiquitination and down-regulation, an effect previously observed by deletion of the entire C1A domain. Molecular dynamics (MD) simulations and analysis of stable regions of the domain using local spatial pattern (LSP) alignment suggested that P42 interacts with Q66 to impair mobility and conformation of one of the ligand-binding loops. Additional mutation of Q66 to the smaller asparagine (R42P\/Q66N), to remove conformational constraints, restored degradation sensitivity. Our results unveil how disease-associated mutations of the same residue in the C1A domain can toggle between gain- or loss-of-function of PKC.<\/jats:p>","DOI":"10.1042\/bcj20220397","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T04:46:08Z","timestamp":1691469968000},"page":"1299-1316","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Single-residue mutation in protein kinase C toggles between cancer and neurodegeneration"],"prefix":"10.1042","volume":"480","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4306-0906","authenticated-orcid":false,"given":"Alexander C.","family":"Jones","sequence":"first","affiliation":[{"name":"1Department of Pharmacology, University of California, La Jolla, CA 92093, U.S.A."},{"name":"2Biomedical Sciences Graduate Program, University of California, La Jolla, CA 92093, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandr P.","family":"Kornev","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology, University of California, La Jolla, CA 92093, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jui-Hung","family":"Weng","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology, University of California, La Jolla, CA 92093, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Manning","sequence":"additional","affiliation":[{"name":"3Nuabio Research, Burlingame, CA 94010, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan S.","family":"Taylor","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology, University of California, La Jolla, CA 92093, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2906-3705","authenticated-orcid":false,"given":"Alexandra C.","family":"Newton","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology, University of California, La Jolla, CA 92093, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"2023082511204494100_BCJ-2022-0397CC1","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1096\/fasebj.9.7.7737456","article-title":"Protein kinase C and lipid signaling for sustained cellular responses","volume":"9","year":"1995","journal-title":"FASEB J."},{"key":"2023082511204494100_BCJ-2022-0397CC2","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1080\/10409238.2018.1442408","article-title":"Protein kinase C: perfectly balanced","volume":"53","year":"2018","journal-title":"Crit. 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