{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:43Z","timestamp":1790833303105,"version":"4.1.0"},"reference-count":28,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["AG66986"],"award-info":[{"award-number":["AG66986"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM 122894"],"award-info":[{"award-number":["GM 122894"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jbc.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Biological Chemistry"],"published-print":{"date-parts":[[2021,1]]},"DOI":"10.1016\/j.jbc.2021.100281","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T05:26:37Z","timestamp":1610515597000},"page":"100281","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":74,"special_numbering":"C","title":["Familial Alzheimer\u2019s disease mutations in amyloid protein precursor alter proteolysis by \u03b3-secretase to increase amyloid \u03b2-peptides of \u226545 residues"],"prefix":"10.1016","volume":"296","author":[{"given":"Sujan","family":"Devkota","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd D.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5721-9092","authenticated-orcid":false,"given":"Michael S.","family":"Wolfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jbc.2021.100281_bib1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1056\/NEJMra0909142","article-title":"Alzheimer's disease","volume":"362","author":"Querfurth","year":"2010","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.jbc.2021.100281_bib2","doi-asserted-by":"crossref","first-page":"29621","DOI":"10.1074\/jbc.R800015200","article-title":"The role of APP processing by BACE1, the \u03b2-secretase, in Alzheimer's disease pathophysiology","volume":"283","author":"Cole","year":"2008","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2021.100281_bib3","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1021\/acs.biochem.9b00401","article-title":"Structure and function of the \u03b3-secretase complex","volume":"58","author":"Wolfe","year":"2019","journal-title":"Biochemistry"},{"key":"10.1016\/j.jbc.2021.100281_bib4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0896-6273(94)90458-8","article-title":"Visualization of A\u03b242(43) and A\u03b240 in senile plaques with end-specific A\u03b2 monoclonals: Evidence that an initially deposited species is A\u03b242(43)","volume":"13","author":"Iwatsubo","year":"1994","journal-title":"Neuron"},{"key":"10.1016\/j.jbc.2021.100281_bib5","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a006296","article-title":"The genetics of Alzheimer disease","volume":"2","author":"Tanzi","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"10.1016\/j.jbc.2021.100281_bib6","doi-asserted-by":"crossref","first-page":"E476","DOI":"10.1073\/pnas.1618657114","article-title":"Analysis of 138 pathogenic mutations in presenilin-1 on the in\u00a0vitro production of A\u03b242 and A\u03b240 peptides by \u03b3-secretase","volume":"114","author":"Sun","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2021.100281_bib7","doi-asserted-by":"crossref","first-page":"35235","DOI":"10.1074\/jbc.C100357200","article-title":"Distinct intramembrane cleavage of the \u03b2-amyloid precursor protein family resembling \u03b3-secretase-like cleavage of Notch","volume":"276","author":"Gu","year":"2001","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2021.100281_bib8","doi-asserted-by":"crossref","first-page":"13042","DOI":"10.1523\/JNEUROSCI.2362-09.2009","article-title":"\u03b3-Secretase: Successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment","volume":"29","author":"Takami","year":"2009","journal-title":"J.\u00a0Neurosci."},{"key":"10.1016\/j.jbc.2021.100281_bib9","doi-asserted-by":"crossref","first-page":"31043","DOI":"10.1074\/jbc.M114.581165","article-title":"Alzheimer presenilin-1 mutations dramatically reduce trimming of long amyloid \u03b2-peptides (A\u03b2) by \u03b3-secretase to increase 42-to-40-residue A\u03b2","volume":"289","author":"Fernandez","year":"2014","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2021.100281_bib10","doi-asserted-by":"crossref","first-page":"9023","DOI":"10.1021\/bi2007146","article-title":"Dissociation between the processivity and total activity of \u03b3-secretase: Implications for the mechanism of Alzheimer's disease-causing presenilin mutations","volume":"50","author":"Quintero-Monzon","year":"2011","journal-title":"Biochemistry"},{"key":"10.1016\/j.jbc.2021.100281_bib11","doi-asserted-by":"crossref","first-page":"6138","DOI":"10.1073\/pnas.110126897","article-title":"Presenilin 1 is linked with \u03b3-secretase activity in the detergent solubilized state","volume":"97","author":"Li","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2021.100281_bib12","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.17578","article-title":"The amyloid-\u03b2 forming tripeptide cleavage mechanism of \u03b3-secretase","volume":"5","author":"Bolduc","year":"2016","journal-title":"eLife"},{"key":"10.1016\/j.jbc.2021.100281_bib13","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/nature13567","article-title":"Three-dimensional structure of human \u03b3-secretase","volume":"512","author":"Lu","year":"2014","journal-title":"Nature"},{"key":"10.1016\/j.jbc.2021.100281_bib14","doi-asserted-by":"crossref","first-page":"23639","DOI":"10.1074\/jbc.M704601200","article-title":"\u03b3-Secretase substrate concentration modulates the A\u03b242\/A\u03b240 ratio: Implications for Alzheimer's Disease","volume":"282","author":"Yin","year":"2007","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2021.100281_bib15","doi-asserted-by":"crossref","first-page":"24294","DOI":"10.1074\/jbc.M211161200","article-title":"Potential link between amyloid \u03b2-protein 42 and C-terminal fragment \u03b349-99 of \u03b2-amyloid precursor protein","volume":"278","author":"Sato","year":"2003","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2021.100281_bib16","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1038\/ncomms3246","article-title":"Alzheimer's disease mutations in APP but not \u03b3-secretase modulators affect \u03b5-cleavage-dependent AICD production","volume":"4","author":"Dimitrov","year":"2013","journal-title":"Nat. Commun."},{"key":"10.1016\/j.jbc.2021.100281_bib17","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.bpj.2014.12.045","article-title":"Intramembrane proteolysis of \u03b2-amyloid precursor protein by \u03b3-secretase is an unusually slow process","volume":"108","author":"Kamp","year":"2015","journal-title":"Biophys. J."},{"key":"10.1016\/j.jbc.2021.100281_bib18","doi-asserted-by":"crossref","first-page":"E509","DOI":"10.1073\/pnas.1512952113","article-title":"Nicastrin functions to sterically hinder \u03b3-secretase-substrate interactions driven by substrate transmembrane domain","volume":"113","author":"Bolduc","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jbc.2021.100281_bib19","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.cell.2013.10.053","article-title":"Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity","volume":"155","author":"Dickey","year":"2013","journal-title":"Cell"},{"key":"10.1016\/j.jbc.2021.100281_bib20","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/nn.2858","article-title":"Potent amyloidogenicity and pathogenicity of A\u03b243","volume":"14","author":"Saito","year":"2011","journal-title":"Nat. Neurosci."},{"key":"10.1016\/j.jbc.2021.100281_bib21","doi-asserted-by":"crossref","first-page":"458","DOI":"10.15252\/emmm.201505952","article-title":"Generation and deposition of A\u03b243 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease","volume":"8","author":"Kretner","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"10.1016\/j.jbc.2021.100281_bib22","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.neuron.2016.03.010","article-title":"Familial Alzheimer's disease mutations in presenilin generate amyloidogenic A\u03b2 peptide seeds","volume":"90","author":"Veugelen","year":"2016","journal-title":"Neuron"},{"key":"10.1016\/j.jbc.2021.100281_bib23","doi-asserted-by":"crossref","first-page":"5675","DOI":"10.1021\/acs.biochem.6b00718","article-title":"Transmembrane substrate determinants for \u03b3-secretase processing of APP CTF\u03b2","volume":"55","author":"Fernandez","year":"2016","journal-title":"Biochemistry"},{"key":"10.1016\/j.jbc.2021.100281_bib24","doi-asserted-by":"crossref","first-page":"14776","DOI":"10.1074\/jbc.M513453200","article-title":"Equimolar production of amyloid \u03b2-protein and amyloid precursor protein intracellular domain from \u03b2-carboxyl-terminal fragment by \u03b3-secretase","volume":"281","author":"Kakuda","year":"2006","journal-title":"J.\u00a0Biol. Chem."},{"key":"10.1016\/j.jbc.2021.100281_bib25","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1523\/JNEUROSCI.1575-04.2005","article-title":"Longer forms of amyloid \u03b2 protein: Implications for the mechanism of intramembrane cleavage by \u03b3-secretase","volume":"25","author":"Qi-Takahara","year":"2005","journal-title":"J.\u00a0Neurosci."},{"key":"10.1016\/j.jbc.2021.100281_bib26","doi-asserted-by":"crossref","first-page":"9774","DOI":"10.1021\/bi0494976","article-title":"Purification and characterization of the human \u03b3-secretase complex","volume":"43","author":"Fraering","year":"2004","journal-title":"Biochemistry"},{"key":"10.1016\/j.jbc.2021.100281_bib27","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.jmb.2008.10.078","article-title":"Cryoelectron microscopy structure of purified \u03b3-secretase at 12 \u00c5 resolution","volume":"385","author":"Osenkowski","year":"2009","journal-title":"J.\u00a0Mol. Biol."},{"key":"10.1016\/j.jbc.2021.100281_bib28","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/bs.mie.2016.10.026","article-title":"Enzymatic assays for studying intramembrane proteolysis","volume":"584","author":"Bolduc","year":"2017","journal-title":"Methods Enzymol."}],"container-title":["Journal of Biological Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925821000491?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925821000491?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T03:05:59Z","timestamp":1634439959000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0021925821000491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":28,"alternative-id":["S0021925821000491"],"URL":"https:\/\/doi.org\/10.1016\/j.jbc.2021.100281","relation":{},"ISSN":["0021-9258"],"issn-type":[{"value":"0021-9258","type":"print"}],"subject":[],"published":{"date-parts":[[2021,1]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Familial Alzheimer\u2019s disease mutations in amyloid protein precursor alter proteolysis by \u03b3-secretase to increase amyloid \u03b2-peptides of \u226545 residues","name":"articletitle","label":"Article Title"},{"value":"Journal of Biological Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jbc.2021.100281","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.","name":"copyright","label":"Copyright"}],"article-number":"100281"}}