The dynamic conformational landscape of γ-secretase
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 complex-specific nanobody, yielding highly pure a...
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| Format: | Online |
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The Company of Biologists
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311135/ |
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pubmed-43111352015-02-24 The dynamic conformational landscape of γ-secretase Elad, Nadav De Strooper, Bart Lismont, Sam Hagen, Wim Veugelen, Sarah Arimon, Muriel Horré, Katrien Berezovska, Oksana Sachse, Carsten Chávez-Gutiérrez, Lucía Research Article 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 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 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. The Company of Biologists 2015-02-01 /pmc/articles/PMC4311135/ /pubmed/25501811 http://dx.doi.org/10.1242/jcs.164384 Text en © 2015. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Elad, Nadav De Strooper, Bart Lismont, Sam Hagen, Wim Veugelen, Sarah Arimon, Muriel Horré, Katrien Berezovska, Oksana Sachse, Carsten Chávez-Gutiérrez, Lucía |
| spellingShingle |
Elad, Nadav De Strooper, Bart Lismont, Sam Hagen, Wim Veugelen, Sarah Arimon, Muriel Horré, Katrien Berezovska, Oksana Sachse, Carsten Chávez-Gutiérrez, Lucía The dynamic conformational landscape of γ-secretase |
| author_facet |
Elad, Nadav De Strooper, Bart Lismont, Sam Hagen, Wim Veugelen, Sarah Arimon, Muriel Horré, Katrien Berezovska, Oksana Sachse, Carsten Chávez-Gutiérrez, Lucía |
| author_sort |
Elad, Nadav |
| title |
The dynamic conformational landscape of γ-secretase |
| title_short |
The dynamic conformational landscape of γ-secretase |
| title_full |
The dynamic conformational landscape of γ-secretase |
| title_fullStr |
The dynamic conformational landscape of γ-secretase |
| title_full_unstemmed |
The dynamic conformational landscape of γ-secretase |
| title_sort |
dynamic conformational landscape of γ-secretase |
| description |
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 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 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. |
| publisher |
The Company of Biologists |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311135/ |
| _version_ |
1613182299044577280 |