2. Academic Validation
  3. Recognition of the amyloid precursor protein by human γ-secretase

Recognition of the amyloid precursor protein by human γ-secretase

  • Science. 2019 Feb 15;363(6428):eaaw0930. doi: 10.1126/science.aaw0930.
Rui Zhou # 1,  Guanghui Yang # 1,  Xuefei Guo 1,  Qiang Zhou 2 3,  Jianlin Lei 1 4,  Yigong Shi 5 2
Affiliations

Affiliations

  • 1 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 Institute of Biology, Westlake Institute for Advanced Study, Westlake University, 18 Shilongshan Road, Xihu District, Hangzhou 310024, Zhejiang Province, China.
  • 3 School of Life Sciences, Westlake University, 18 Shilongshan Road, Xihu District, Hangzhou 310024, Zhejiang Province, China.
  • 4 Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 5 Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. [email protected].
  • # Contributed equally.
PMID: 30630874 DOI: 10.1126/science.aaw0930
Abstract

Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase is linked to Alzheimer's disease (AD). We report an atomic structure of human γ-secretase in complex with a transmembrane (TM) APP fragment at 2.6-angstrom resolution. The TM helix of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of γ-secretase). A hybrid β sheet, which is formed by a β strand from APP and two β strands from PS1, guides γ-secretase to the scissile peptide bond of APP between its TM and β strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of γ-secretase bound to Notch, reveal contrasting features of substrate binding, which may be applied toward the design of substrate-specific inhibitors.

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