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Three-dimensional structure of human γ-secretase
Open accessAbstract
The γ-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-β, which accumulates in the brain and consequently causes Alzheimer’s disease. Here we report the three-dimensional structure of an intact human γ-secretase complex at 4.5 Å resolution, determined by cryo-electron-microscopy single-particle analysis. The γ-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 γ-secretase complex.
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Metadata
- Authors
- Lu, P., Bai, X.-C., Ma, D., Xie, T., Yan, C., Sun, L., Yang, G., Zhao, Y., Zhou, R., Scheres, S. H. W., & Shi, Y.
- Venue
- Nature
- Published
- 2014-06-29
- Volume
- 512
- Issue
- 7513
- Pages
- 166-170
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1552188451
- Cited by
- 346
- References
- 5
- FWCI
- 32.07
- Type
- journal article
- Language
- en
- Open access
- green
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