Three-dimensional structure of human γ-secretase

Peilong Lu, Xiao Chen Bai, Dan Ma, Tian Xie, Chuangye Yan, Linfeng Sun, Guanghui Yang, Yanyu Zhao, Rui Zhou, Sjors H W Scheres, Yigong Shi

Research output: Contribution to journalArticle

206 Scopus citations

Abstract

The γ-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is amembrane-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 4.5A° resolution, determinedbycryo-electron-microscopysingle- particleanalysis.Thec-secretase complexcomprises a horseshoeshaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) fromnicastrin, which sitsimmediately above the hollow space formedby theTMhorseshoe. 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.

Original languageEnglish (US)
Pages (from-to)166-170
Number of pages5
JournalNature
Volume512
Issue number7513
DOIs
StatePublished - Aug 14 2014

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Three-dimensional structure of human γ-secretase'. Together they form a unique fingerprint.

  • Cite this

    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. (2014). Three-dimensional structure of human γ-secretase. Nature, 512(7513), 166-170. https://doi.org/10.1038/nature13567