P2-057: Interactome analyses of mature gamma-secretase complexes reveals distinct molecular environments of presenilin paralogs and preferential binding of signal peptide peptidase to PS2

γ-Secretase plays a pivotal role in the production of neurotoxic amyloid β-peptides (Aβ) in Alzheimer's 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 elucidate whether PS mutations associated with early-onset AD affect the molecular environment of mature γ-secretase complexes and understand the causes for distinct phenotypes of PS paralog deficient mice, 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 (TAP) 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 macro-complex 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 (SPP), predominantly co-purified with PS2-containing γ-secretase complexes and was observed to influence Aβ production. The study confirmed the anticipation that a majority of presenilin candidate interactors associate with both PS1- and PS2-containing γ-secretase complexes but also revealed for the first time a small number of proteins that co-purified in a PS paralog-specific manner. It remains to be seen if the surprising association of PS2 and SPP serves the purpose to facilitate rapid removal of transmembrane stubs embedded in the lipid bilayer with opposite topologies.