The dynamic conformational landscape of γ-secretase

Nadav Elad, Bart de Strooper, Sam Lismont, Wim Hagen, Sarah Veugelen, Muriel Arimon, Katrien Horré, Oksana Berezovska, Carsten Sachse, Luciá Chávez-Gutiérrez

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

The structure and function of the γ-secretase proteases are of great interest because of their crucial roles in cellular and disease processes. We established a novel purification protocol for the γ-secretase complex that involves a conformation- and complexspecific 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 differ in overall compactness and relative position of the nicastrin ectodomain. Occupancy of the active or substrate-binding sites by inhibitors differentially stabilizes subpopulations of particles with compact conformations, whereas a mutation linked to familial Alzheimer disease results in enrichment of extended-conformation complexes with increased flexibility. Our study presents the γ-secretase complex as a dynamic population of interconverting conformations, involving rearrangements at the nanometer scale and a high level of structural interdependence between subunits. The fact that protease inhibition or clinical mutations, which affect amyloid β (Aβ) generation, enrich for particular subpopulations of conformers indicates the functional relevance of the observed dynamic changes, which are likely to be instrumental for highly allosteric behavior of the enzyme.

Original languageEnglish
Pages (from-to)589-598
Number of pages10
JournalJournal of Cell Science
Volume128
Issue number3
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Alzheimer disease
  • Conformational landscape
  • Regulated intramembrane proteolysis
  • Single particle electron microscopy
  • γ-secretase

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