Journal
NATURE
Volume 512, Issue 7513, Pages 166-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13567
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Funding
- Ministry of Science and Technology of China [2009CB918801]
- National Natural Science Foundation of China [30888001, 31021002, 31130002]
- European Union Marie Curie Fellowship
- UK Medical Research Council [MC_UP_A025_1013]
- MRC [MC_UP_A025_1013] Funding Source: UKRI
- Medical Research Council [MC_UP_A025_1013] Funding Source: researchfish
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The gamma-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Aberrant cleavage of the amyloid precursor protein (APP) results in aggregation of amyloid-beta, which accumulates in the brain and consequently causes Alzheimer's disease. Here we report the three-dimensional structure of an intact human gamma-secretase complex at 4.5 angstrom resolution, determined by cryo-electron-microscopy single-particle analysis. The gamma-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) from nicastrin, which sits immediately above the hollow space formed by the TM horseshoe. Intriguingly, nicastrin ECD is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA. This structure serves as an important basis for understanding the functional mechanisms of the gamma-secretase complex.
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