Interactome Analyses of Mature γ-Secretase Complexes Reveal Distinct Molecular Environments of Presenilin (PS) Paralogs and Preferential Binding of Signal Peptide Peptidase to PS2

• Published in: The Journal of biological chemistry 2013-05, Vol.288 (21), p.15352-15366
• Main Authors: Jeon, Amy Hye Won, Böhm, Christopher, Chen, Fusheng, Huo, Hairu, Ruan, Xueying, Ren, Carl He, Ho, Keith, Qamar, Seema, Mathews, Paul M., Fraser, Paul E., Mount, Howard T.J., St George-Hyslop, Peter, Schmitt-Ulms, Gerold
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimers Disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - immunology; Animals; Cadherins - genetics; Cadherins - metabolism; Catenins - genetics; Catenins - metabolism; Genomics and Proteomics; HEK293 Cells; Humans; Interactome; Mass Spectrometry (MS); Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Mutation; Presenilin; Presenilin-2 - genetics; Presenilin-2 - metabolism; Protein Binding - genetics; Proteomics; Secretases; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Transgenic; Vacuolar Proton-Translocating ATPases - genetics; Vacuolar Proton-Translocating ATPases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.441840

γ-Secretase plays a pivotal role in the production of neurotoxic amyloid β-peptides (Aβ) in Alzheimer disease (AD) and consists of a heterotetrameric core complex that includes the aspartyl intramembrane protease presenilin (PS). The human genome codes for two presenilin paralogs. To understand the causes for distinct phenotypes of PS paralog-deficient mice and elucidate whether PS mutations associated with early-onset AD affect the molecular environment of mature γ-secretase complexes, quantitative interactome comparisons were undertaken. Brains of mice engineered to express wild-type or mutant PS1, or HEK293 cells stably expressing PS paralogs with N-terminal tandem-affinity purification tags served as biological source materials. The analyses revealed novel interactions of the γ-secretase core complex with a molecular machinery that targets and fuses synaptic vesicles to cellular membranes and with the H+-transporting lysosomal ATPase macrocomplex but uncovered no differences in the interactomes of wild-type and mutant PS1. The catenin/cadherin network was almost exclusively found associated with PS1. Another intramembrane protease, signal peptide peptidase, predominantly co-purified with PS2-containing γ-secretase complexes and was observed to influence Aβ production. Background: The human genome codes for two presenilin (PS) paralogs, PS1 and PS2. Results: PS paralogs are embedded in overlapping but distinct molecular environments, with signal peptide peptidase (SPP) primarily binding to PS2. Conclusion: Study paves the way for understanding functional divergence of PS paralogs. Significance: Example of an interaction between a Type I- and Type II-directed intramembrane protease.