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dc.contributor.authorHemming, Matthew Louis
dc.contributor.authorElias, Joshua E
dc.contributor.authorGygi, Steven P.
dc.contributor.authorSelkoe, Dennis J.
dc.date.accessioned2011-11-09T17:40:06Z
dc.date.issued2008
dc.identifier.citationHemming, Matthew L., Joshua E. Elias, Steven P. Gygi, and Dennis J. Selkoe. 2008. Proteomic Profiling of γ-Secretas Substrates and Mapping of Substrate Requirements. PLoS Biology 6(10): e257.en_US
dc.identifier.issn1544-9173en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5343428
dc.description.abstractThe presenilin/γ-secretase complex, an unusual intramembrane aspartyl protease, plays an essential role in cellular signaling and membrane protein turnover. Its ability to liberate numerous intracellular signaling proteins from the membrane and also mediate the secretion of amyloid-β protein (Aβ) has made modulation of γ-secretase activity a therapeutic goal for cancer and Alzheimer disease. Although the proteolysis of the prototypical substrates Notch and β-amyloid precursor protein (APP) has been intensely studied, the full spectrum of substrates and the determinants that make a transmembrane protein a substrate remain unclear. Using an unbiased approach to substrate identification, we surveyed the proteome of a human cell line for targets of γ-secretase and found a relatively small population of new substrates, all of which are type I transmembrane proteins but have diverse biological roles. By comparing these substrates to type I proteins not regulated by γ-secretase, we determined that besides a short ectodomain, γ-secretase requires permissive transmembrane and cytoplasmic domains to bind and cleave its substrates. In addition, we provide evidence for at least two mechanisms that can target a substrate for γ cleavage: one in which a substrate with a short ectodomain is directly cleaved independent of sheddase association, and a second where a substrate requires ectodomain shedding to instruct subsequent γ-secretase processing. These findings expand our understanding of the mechanisms of substrate selection as well as the diverse cellular processes to which γ-secretase contributes.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pbio.0060257en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570425/pdf/en_US
dash.licenseLAA
dc.subjectbiochemistryen_US
dc.subjectbiotechnologyen_US
dc.subjectcell biologyen_US
dc.subjectmolecular biologyen_US
dc.subjectneurological disordersen_US
dc.titleProteomic Profiling of γ-Secretase Substrates and Mapping of Substrate Requirementsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Biologyen_US
dash.depositing.authorHemming, Matthew Louis
dc.date.available2011-11-09T17:40:06Z
dash.affiliation.otherHMS^Stipendees - Enrichment Programs Stipen_US
dash.affiliation.otherHMS^Neurology-Brigham and Women's Hospitalen_US
dash.affiliation.otherHMS^Stipendees - Div of Medical Sciencesen_US
dash.affiliation.otherHMS^Cell Biologyen_US
dash.affiliation.otherHMS^Neurology-Brigham and Women's Hospitalen_US
dc.identifier.doi10.1371/journal.pbio.0060257*
dash.contributor.affiliatedHemming, Matthew
dash.contributor.affiliatedSelkoe, Dennis
dash.contributor.affiliatedGygi, Steven


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