γ-Secretase, an aspartyl protease that belongs to the iCLiPs (intramembrane cleaving proteases) family, is a multiprotein complex that consists of presenilin (PS), nicastrin (NCT), Aph-1 and Pen-2 (ref. 1). It is responsible for generation of the β-amyloid peptide (Aβ), the primary component of senile plaques in the brains of patients with Alzheimer's disease. Although the four components are necessary and sufficient for γ-secretase activity2,3,4, additional proteins are possibly involved in its regulation. Consequently, we purified proteins associated with the active γ-secretase complex from reconstituted PS-deficient fibroblasts, using tandem affinity purification (TAP)5 and identified a series of proteins that transiently interact with the γ-secretase complex and are probably involved in complex maturation, membrane trafficking and, importantly, the tetraspanin web. Tetraspanins form detergent-resistant microdomains in the cell membrane and regulate cell adhesion, cell signalling and proteolysis6,7. Association of the γ-secretase complex with tetraspanin-enriched microdomains provides an explanation for the previously documented localization of γ-secretase to raft-like domains8. Thus, these studies suggest that maintenance of the integrity of tetraspanin microdomains contributes to the refinement of proteolytic activity of the γ-secretase complex.
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We thank T. E. Golde (Mayo Clinic, FL, US) for SPPL3 cDNA, S. Aerts (VIB), E. Karran and the bioinformatics team of Elli-Lilly for helpful discussion and A. Thathiah for critical reading of the manuscript. This work was supported by a Pioneer award from the Alzheimer's Association, the Fund for Scientific Research, Flanders; Katholieke Universiteit Leuven (GOA); Federal Office for Scientific Affairs (IUAP P6/58) and a Methusalem grant from the Flemisch government. The laboratory in Ghent is supported by research grants from the Fund for Scientific Research – Flanders (Belgium), the Concerted Research Actions (GOA) from the Ghent University, the Inter University Attraction Poles (IUAP06) and the European Union Interaction Proteome (6th Framework Program). L.B. is fellow of the FWO (Fonds voor Wetenschappelijk Onderzoek) and T.W. was fellow of the Canon Foundation in Europe and Marie Curie program of the EC.
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Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms
Journal of Neurochemistry (2019)