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First published online February 6, 2008
doi: 10.1242/10.1242/jcs.015255

Journal of Cell Science 121, 413-420 (2008)
Published by The Company of Biologists 2008
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Commentary

Building {gamma}-secretase – the bits and pieces

Dragana Spasic and Wim Annaert*

Laboratory for Membrane Trafficking, Center for Human Genetics (KULeuven) and Department of Molecular and Developmental Genetics (VIB), O&N1, Rm. 9.696, Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

* Author for correspondence (e-mail: Willem.Annaert{at}med.kuleuven.be)

Accepted 13 December 2007

{gamma}-Secretase is a promiscuous aspartyl protease responsible for the final intramembrane cleavage of various type I transmembrane proteins after their large ectodomains are shed. The vast functional diversity of its substrates, which are involved in cell fate decisions, adhesion, neurite outgrowth and synapse formation, highlights the important role {gamma}-secretase plays in development and neurogenesis. The most renowned substrates are the amyloid precursor protein and Notch, from which {gamma}-secretase liberates amyloid β peptides and induces downstream signalling, respectively. {gamma}-Secretase is a multiprotein complex containing presenilin (which harbours the catalytic site), nicastrin, APH1 and PEN2. Its assembly occurs under tight control of ER-Golgi recycling regulators, which allows defined quantities of complexes to reach post-Golgi compartments, where {gamma}-secretase activity is regulated by multiple other factors. 3D-EM rendering reveals a complex with a translucent inner space, suggesting the presence of a water-filled cavity required for intramembrane proteolysis. Despite huge efforts, we are now only beginning to unravel the assembly, stoichiometry, activation and subcellular location of {gamma}-secretase.

Key words: ER-Golgi transport, Gamma-secretase, Intramembrane proteolysis






© The Company of Biologists Ltd 2008