Nicastrin interacts with γ-secretase complex components via the N-terminal part of its transmembrane domain
J Biol Chem 278(52): 52519-23
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Two secretases are involved in the generation of amyloid β-peptide, the principal component of amyloid plaques in the brains of Alzheimer's disease patients. While β-secretase is a classical aspartyl protease, γ-secretase activity is associated with a high molecular weight complex. One of the complex components, which is critically required for γ-secretase activity is nicastrin (NCT). Here we investigate the assembly of NCT into the γ-secretase complex. NCT mutants either lacking the entire cytoplasmic tail, the cytoplasmic tail, and the transmembrane domain (TMD), or containing a set of heterologous TMDs were expressed in cells with strongly reduced levels of endogenous NCT. Maturation of exogenous NCT, γ-secretase complex formation and proteolytic function was then investigated. This revealed that the cytoplasmic tail of NCT is dispensable for γ-secretase complex assembly and function. In contrast, the authentic TMD of NCT is critically required for the interaction with γ-secretase complex components and for formation of an active γ-secretase complex. Neither soluble NCT lacking any membrane anchor nor NCT containing a heterologous TMD were inserted into the γ-secretase complex. We identified the N-terminal region of the NCT TMD as a functionally important entity of NCT. These data thus demonstrate that NCT interacts with other γ-secretase complex components via its TMD.