Identification of β-Secretase (BACE1) Substrates Using Quantitative Proteomics

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Identification of β-Secretase (BACE1) Substrates Using Quantitative Proteomics

Show simple item record Elias, Joshua E. Maas, Stefan Gygi, Steven P. Selkoe, Dennis J. Hemming, Matthew Louis 2012-03-01T01:35:47Z 2009
dc.identifier.citation Hemming, Matthew L., Joshua E. Elias, Steven P. Gygi, and Dennis J. Selkoe. 2009. Identification of β-Secretase (BACE1) substrates using quantitative proteomics. PLoS ONE 4(12): e8477. en_US
dc.identifier.issn 1932-6203 en_US
dc.description.abstract β-site APP cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease with a lumenal active site that sheds the ectodomains of membrane proteins through juxtamembrane proteolysis. BACE1 has been studied principally for its role in Alzheimer's disease as the β-secretase responsible for generating the amyloid-β protein. Emerging evidence from mouse models has identified the importance of BACE1 in myelination and cognitive performance. However, the substrates that BACE1 processes to regulate these functions are unknown, and to date only a few β-secretase substrates have been identified through candidate-based studies. Using an unbiased approach to substrate identification, we performed quantitative proteomic analysis of two human epithelial cell lines stably expressing BACE1 and identified 68 putative β-secretase substrates, a number of which we validated in a cell culture system. The vast majority were of type I transmembrane topology, although one was type II and three were GPI-linked proteins. Intriguingly, a preponderance of these proteins are involved in contact-dependent intercellular communication or serve as receptors and have recognized roles in the nervous system and other organs. No consistent sequence motif predicting BACE1 cleavage was identified in substrates versus non-substrates. These findings expand our understanding of the proteins and cellular processes that BACE1 may regulate, and suggest possible mechanisms of toxicity arising from chronic BACE1 inhibition. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi: 10.1371/journal.pone.0008477 en_US
dc.relation.hasversion en_US
dash.license LAA
dc.title Identification of β-Secretase (BACE1) Substrates Using Quantitative Proteomics en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US Gygi, Steven P. 2012-03-01T01:35:47Z
dash.affiliation.other HMS^Stipendees - Enrichment Programs Stip en_US
dash.affiliation.other HMS^Neurology-Brigham and Women's Hospital en_US
dash.affiliation.other HMS^Stipendees - Div of Medical Sciences en_US
dash.affiliation.other HMS^Cell Biology en_US
dash.affiliation.other HMS^Neurology-Brigham and Women's Hospital en_US

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