Assembly, Trafficking and Function of γ-SecretaseKaether C. · Haass C. · Steiner H.
Laboratory for Alzheimer’s and Parkinson’s Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany
γ-Secretase catalyzes the final cleavage of the β-amyloid precursor protein to generate amyloid-β peptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer’s disease. Here, we review the identification of γ-secretase as a protease complex and its assembly and trafficking to its site(s) of cellular function. In reconstitution experiments, γ-secretase was found to be composed of four integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2 and APH-1 that are essential and sufficient for γ-secretase activity. PS, which serves as a catalytic subunit of γ-secretase, was identified as a prototypic member of novel aspartyl proteases of the GxGD type. In human cells, γ-secretase could be further defined as a heterogeneous activity consisting of distinct complexes that are composed of PS1 or PS2 and APH-1a or APH-1b homologues together with NCT and PEN-2. Using green fluorescent protein as a reporter we localized PS and γ-secretase activity at the plasma membrane and endosomes. Investigation of γ-secretase complex assembly in knockdown and knockout cells of the individual subunits allowed us to develop a model of complex assembly in which NCT and APH-1 first stabilize PS before PEN-2 assembles as the last component. Furthermore, we could map domains in PS and PEN-2 that govern assembly and trafficking of the complex. Finally, Rer1 was identified as a PEN-2-binding protein that serves a role as an auxiliary factor for γ-secretase complex assembly.
Dr. Christoph Kaether
Group ‘Membrane trafficking of proteins involved in Alzheimer’s Disease’
Leibniz Institute for Age Research – Fritz Lipmann Institute
Beutenbergstrasse 11, DE–07745 Jena (Germany)
Tel. +49 3641 65 6230, Fax +49 3641 65 6040, E-Mail email@example.com
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 0, Number of References : 77
Vol. 3, No. 4-5, Year 2006 (Cover Date: October 2006)
Journal Editor: Nitsch, R.M. (Zürich)
ISSN: 1660–2854 (print), 1660–2862 (Online)
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