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Diverse Functions of γ -secretase: Releasing Signaling Fragments and Deleterious Molecules

[ Vol. 9 , Issue. 1 ]

Author(s):

Sun-Ho Han, Chaeyoung Kim and Inhee Mook-Jung   Pages 15 - 27 ( 13 )

Abstract:


γ-secretase is a pleiotropic intramembrane-cleaving protease. It is a multiprotein complex that comprises presnilin (PS), nicastrin (NCT), presnilin enhancer-2 (Pen-2), and anterior pharynx-defective-1 (Aph-1)—all of which are essential for its proteolytic activity. Promiscuously diverse substrates are susceptible to cleavage by γ-secretase, of which amyloid precursor protein (APP) and notch are the well-characterized substrates. Specifically, APP processing by γ - secretase has garnered much attention, because the generation of amyloidogenic amyloid β peptide (Aβ) is the hallmark of the pathogenesis of Alzheimer’s disease (AD). Thus, the regulatory mechanisms and substrate specificities of γ-secretase proteolytic activity have been studied extensively as therapeutic targets of AD. Further, the processing of other substrates has broad biological implications, releasing an intracellular domain that functions as a signaling molecule. Hence, γ - secretase regulates many physiological functions and pathologies.

We summarize the current literatures on γ-secretase, including its assembly and substrates. Its diverse substrates and the downstream events that are initiated by the release of the intracellular domains of substrates after γ-secretase cleavage are discussed, as is their significance under normal and aberrant physiological conditions. Further, the regulation of γ - secretase activity is broached to yield insights into using this promiscuous enzyme to develop therapeutic agents for AD.

Keywords:

γ-secretase, amyloid β-peptide (Aβ), Notch, APP, Alzheimer disease.

Affiliation:

Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 28 Yungun-dong, Jongro-gu, Seoul 110-799, Korea.



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