Gamma Secretase - Subunits and Assembly

Subunits and Assembly

The gamma secretase complex has not yet been fully characterized but minimally consists of four individual proteins: presenilin, nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). Recent evidence suggests that a fifth protein, known as CD147, is a non-essential regulator of the complex whose absence increases activity. Presenilin, an aspartyl protease, is the catalytic subunit; mutations in the presenilin gene have been shown to be a major genetic risk factor for Alzheimer's disease. In humans, two forms of presenilin and two forms of APH-1 have been identified in the genome; one of the APH homologs can also be expressed in two isoforms via alternative splicing, leading to at least six different possible gamma secretase complexes that may have tissue- or cell type specificity.

The proteins in the gamma secretase complex are heavily modified by proteolysis during assembly and maturation of the complex; a required activation step is in the autocatalytic cleavage of presenilin to N- and C-terminal fragments. Nicastrin's primary role is in maintaining the stability of the assembled complex and regulating intracellular protein trafficking. PEN-2 associates with the complex via binding of a transmembrane domain of presenilin and, among other possible roles, helps to stabilize the complex after presenilin proteolysis has generated the activated N-terminal and C-terminal fragments. APH-1, which is required for proteolytic activity, binds to the complex via a conserved alpha helix interaction motif and aids in initiating assembly of premature components.

Recent research has shown that interaction of the gamma secretase complex with the γ-secretase activating protein facilitates the gamma cleavage of amyloid precursor protein into β-amyloid.