Structure of γ-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy Journal Article
| Authors: | Renzi, F.; Zhang, X.; Rice, W. J.; Torres-Arancivia, C.; Gomez-Llorente, Y.; Diaz, R.; Ahn, K.; Yu, C.; Li, Y. M.; Sisodia, S. S.; Ubarretxena-Belandia, I. |
| Article Title: | Structure of γ-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy |
| Abstract: | The γ-secretase membrane protein complex is responsible for proteolytic maturation of signaling precursors and catalyzes the final step in the production of the amyloid β-peptides implicated in the pathogenesis of Alzheimer disease. The incorporation of PEN-2 (presenilin enhancer 2) into a pre-activation intermediate, composed of the catalytic subunit presenilin and the accessory proteins APH-1 (anterior pharynx-defective 1) and nicastrin, triggers the endoproteolysis of presenilin and results in an active tetrameric γ-secretase. We have determined the three-dimensional reconstruction of a mature and catalytically active γ-secretase using single-particle cryo-electron microscopy. γ-Secretase has a cup-like shape with a lateral belt of ∼40-50 Å in height that encloses a water-accessible internal chamber. Active site labeling with a gold-coupled transition state analog inhibitor suggested that the γ-secretase active site faces this chamber. Comparison with the structure of a trimeric pre-activation intermediate suggested that the incorporation of PEN-2 might contribute to the maturation of the active site architecture. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | controlled study; human cell; three dimensional; proteins; electron microscopy; embryo; enzyme activity; cell strain hek293; image processing; enzyme structure; alzheimer disease; pre-activation; particle size; nicastrin; gamma secretase; presenilin 2; enzyme active site; presenilins; transition state; secretases; active site; endoproteolysis; active site architecture; catalytic subunits; cryo-electron microscopy; membrane protein complex; single-particle; three-dimensional reconstruction; biological membranes; electron microscopes; single particle cryoelectron microscopy |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 286 |
| Issue: | 24 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2011-06-17 |
| Start Page: | 21440 |
| End Page: | 21449 |
| Language: | English |
| DOI: | 10.1074/jbc.M110.193326 |
| PROVIDER: | scopus |
| PMCID: | PMC3122203 |
| PUBMED: | 21454611 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 17 August 2011" - "CODEN: JBCHA" - "Source: Scopus" |
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