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gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 42 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.
==Subunits and assembly==
The gamma secretase complex consists of four individual proteins: PSEN1 (presenilin-1), 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.
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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