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Structure. 2014 Jan 7;22(1):125-35. doi: 10.1016/j.str.2013.09.018. Epub 2013 Nov 7.

Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.

Author information

1
Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
2
Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada.
3
Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
4
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, and Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Bunkyo-ku, Tokyo 113-0033, Japan.
5
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
6
Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Genetics and Genomics, Biostatistics, and Epidemiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA.
7
Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON M5S 3H2, Canada. Electronic address: phs22@cam.ac.uk.

Abstract

Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors. The complexes are bilobed. The head contains nicastrin ectodomain. The membrane-embedded base has a central channel and a lateral cleft, which may represent the initial substrate docking site. Inhibitor binding induces widespread structural changes, including rotation of the head and closure of the lateral cleft. These changes block substrate access to the catalytic pocket and inhibit the enzyme. Intriguingly, peptide substrate docking has reciprocal effects on the inhibitor binding site. Similar reciprocal shifts may underlie the mechanisms of other inhibitors and of the "lateral gate" through which substrates access to the catalytic site.

PMID:
24210759
PMCID:
PMC3887256
DOI:
10.1016/j.str.2013.09.018
[Indexed for MEDLINE]
Free PMC Article

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