Characterization of the enzymatic properties of γ-secretase

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How the cleavage proceeds within the membrane has long been enigmatic. We previously hypothesized that βCTF is cleaved first at the membrane-cytoplasm boundary, producing two long Ass, Aβ48 and Aβ49, which are processed further by releasing three residues at each step to produce Aβ42 and Aβ40, respectively. To test this hypothesis, we used LC-MS/MS to quantify the specific tripeptides that are postulated to be released. Using CHAPSO-reconstituted γ-secretase system, we confirmed that Aβ49 is converted to Aβ43/40 by successively releasing two or three tripeptides, and that Aβ48 is converted to Aβ42/38 by successively releasing two tripeptides or these plus an additional tetrapeptide.