{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:02:45Z","timestamp":1791277365350,"version":"4.1.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"50","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,12,14]]},"abstract":"<jats:p>\n                    A complex composed of presenilin (PS), nicastrin, PEN-2, and APH-1 is absolutely required for \u03b3-secretase activity in vivo. Evidence has emerged to suggest a role for PS as the catalytic subunit of \u03b3-secretase, but it has not been established that PS is catalytically active in the absence of associated subunits. We now report that bacterially synthesized, recombinant PS (rPS) reconstituted into liposomes exhibits \u03b3-secretase activity. Moreover, an rPS mutant that lacks a catalytic aspartate residue neither exhibits reconstituted \u03b3-secretase activity nor interacts with a transition-state \u03b3-secretase inhibitor. Importantly, we demonstrate that rPS harboring mutations that cause early onset familial Alzheimer\u2019s disease (FAD) lead to elevations in the ratio of A\u03b242 to A\u03b240 peptides produced from a wild-type APP substrate and that rPS enhances the\n                    <jats:italic>A\u03b2<\/jats:italic>\n                    42\/\n                    <jats:italic>A\u03b2<\/jats:italic>\n                    40 peptide ratio from FAD-linked mutant APP substrates, findings that are entirely consistent with the results obtained in in vivo settings. Thus, \u03b3-secretase cleavage specificity is an inherent property of the polypeptide. Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of \u03b3-secretase. Thus, we conclusively establish that activated PS is catalytically competent and the bimolecular interaction of PS1 and PEN2 can convert the PS1 zymogen to an active protease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1013246107","type":"journal-article","created":{"date-parts":[[2010,11,30]],"date-time":"2010-11-30T04:18:15Z","timestamp":1291090695000},"page":"21435-21440","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":129,"title":["Activation and intrinsic \u03b3-secretase activity of presenilin 1"],"prefix":"10.1073","volume":"107","author":[{"given":"Kwangwook","family":"Ahn","sequence":"first","affiliation":[{"name":"Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Shelton","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;"},{"name":"Department of Pharmacology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;"},{"name":"Department of Physiology, Biophysics and Systems Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xulun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Molecular Neurobiology, University of Chicago, Chicago, IL 60637; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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