Proteomic Profiling of γ-Secretase Substrates and Mapping of Substrate Requirements

DSpace/Manakin Repository

Proteomic Profiling of γ-Secretase Substrates and Mapping of Substrate Requirements

Citable link to this page

. . . . . .

Title: Proteomic Profiling of γ-Secretase Substrates and Mapping of Substrate Requirements
Author: Elias, Joshua E; Hemming, Matthew Louis; Gygi, Steven P.; Selkoe, Dennis J.

Note: Order does not necessarily reflect citation order of authors.

Citation: Hemming, 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.
Full Text & Related Files:
Abstract: The 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.
Published Version: doi:10.1371/journal.pbio.0060257
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570425/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:5343428

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters