Title: The dynamic conformational landscape of γ-secretase
Authors: Elad, Nadav ×
De Strooper, Bart
Lismont, Sam
Hagen, Wim
Veugelen, Sarah
Arimon, Muriel
Horré, Katrien
Berezovska, Oksana
Sachse, Carsten
Chavez Gutierrez, Lucia #
Issue Date: Feb-2015
Publisher: Co. of Biologists
Series Title: Journal of Cell Science vol:128 issue:3 pages:589-98
Article number: jcs.164384
Abstract: The structure and function of the γ-secretase proteases are of vast interest because of their critical roles in cellular and disease processes. We established a novel purification protocol for γ-secretase complex that involves a conformation and complex-specific nanobody, yielding highly pure and active enzyme. Using single particle electron microscopy, we analyzed the γ-secretase structure and its conformational variability. Under steady state conditions the complex adopts three major conformations, which are different in overall compactness and relative position of the nicastrin ectodomain. Occupancy of the active or substrate binding sites by inhibitors differentially stabilize sub-populations of particles with compact conformations, whereas a Familial Alzheimer Disease-linked mutation results in enrichment of extended-conformation complexes with increased flexibility. Our study presents the γ-secretase complex as a dynamic population of inter-converting conformations, involving rearrangements at the nanometer scale and high level of structural interdependence between subunits. The fact that protease inhibition or clinical mutations, which affect Aβ generation, enrich for particular subpopulations of conformers indicates the functional relevance of the observed dynamic changes, which are likely instrumental for highly allosteric behavior of the enzyme.
ISSN: 0021-9533
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Elad et al_J Cell Sci 2014.pdfmain article Accepted 2588KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science