期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 24, 页码 21440-21449出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.193326
关键词
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资金
- National Institutes of Health [R01 AG027854-01A1, R01 AG026660]
- European Community
- Alzheimer's Association [IIRG-06-26572]
- American Health Assistance Foundation
- National Science Foundation [MCB-0546087]
The gamma-secretase membrane protein complex is responsible for proteolytic maturation of signaling precursors and catalyzes the final step in the production of the amyloid beta-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 gamma-secretase. We have determined the three-dimensional reconstruction of a mature and catalytically active gamma-secretase using single-particle cryo-electron microscopy. gamma-Secretase has a cup-like shape with a lateral belt of similar to 40-50 angstrom in height that encloses a water-accessible internal chamber. Active site labeling with a gold-coupled transition state analog inhibitor suggested that the gamma-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.
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