Uncovering ggr-Secretase

Author: Harald Steiner1

Source: Current Alzheimer Research, Volume 1, Number 3, August 2004 , pp. 175-181(7)

Publisher: Bentham Science Publishers

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Abstract:

Accumulation of the amyloid bgr-peptide (Abgr) in the brain is believed to initiate a series of neurotoxic events that causes neurodegeneration in Alzheimer´s disease (AD). Abgr is generated by processing of the bgr-amyloid precursor protein (APP) through the successive action of two proteolytic enzymes, bgr-secretase and ggr-secretase. While bgr-secretase has been identified as the membrane-bound aspartyl protease BACE, the identity of ggr-secretase, which catalyzes the final, intramembrane cleavage of APP as well as of several other type I transmembrane proteins, has been enigmatic for a long time. Exciting progress has been made in the past year towards its uncovering. Genetics paved the way for subsequent biochemical reconstitution studies that demonstrated that ggr-secretase is a protein complex composed of presenilin (PS), nicastrin (NCT), APH-1 and PEN-2. Thus, the complete set of genes that is required to generate Abgr from its precursor has now ultimately been identified. PS carries the active site of ggr-secretase and is a founding member of a novel class of polytopic aspartyl proteases that utilize a non-classical active site to cleave their membrane-tethered substrates. The other components are required for assembly, stabilization and maturation of the complex and NCT may be involved in the recognition of ggr-secretase substrates.

Keywords: alzheimer's disease; amyloid peptide; aph-1; nicastrin; nicastrin; pen-2; presenilin; secretase; secretase complex

Document Type: Review article

DOI: 10.2174/1567205043332081

Affiliations: 1: Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Schillerstr. 44, Ludwig-Maximilians-University, 80336 Munich, Germany.

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