Structural and Chemical Biology of Presenilin Complexes
- 1Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139
- 2Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065
- 3Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrookes Hospital, Cambridge CB2 0XY, United Kingdom
- 4Tanz Centre for Research in Neurodegenerative Diseases and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, Ontario M5T 2S8, Canada
- Correspondence: phs22{at}cam.ac.uk
Abstract
The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of γ-secretase modulator (GSM) compounds that modulate the relative efficiency of γ, ɛ, ζ site cleavage and/or substrate specificity.
