4uis Citations

Structural basis of human γ-secretase assembly.

OpenAccess logo Proc Natl Acad Sci U S A 112 6003-8 (2015)
Cited: 56 times
EuropePMC logo PMID: 25918421

Abstract

The four-component intramembrane protease γ-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of γ-secretase remain to be specifically assigned. Here we report a 3D structure of human γ-secretase at 4.32-Å resolution, determined by single-particle, electron cryomicroscopy in the presence of digitonin and with a T4 lysozyme fused to the amino terminus of presenilin 1 (PS1). The overall structure of this human γ-secretase is very similar to that of wild-type γ-secretase determined in the presence of amphipols. The 20 TMs are unambiguously assigned to the four components, revealing principles of subunit assembly. Within the transmembrane region, PS1 is centrally located, with its amino-terminal fragment (NTF) packing against Pen-2 and its carboxyl-terminal fragment (CTF) interacting with Aph-1. The only TM of nicastrin associates with Aph-1 at the thick end of the TM horseshoe, and the extracellular domain of nicastrin directly binds Pen-2 at the thin end. TM6 and TM7 in PS1, which harbor the catalytic aspartate residues, are located on the convex side of the TM horseshoe. This structure serves as an important framework for understanding the function and mechanism of γ-secretase.

Articles - 4uis mentioned but not cited (8)

  1. Structural basis of human γ-secretase assembly. Sun L, Zhao L, Yang G, Yan C, Zhou R, Zhou X, Xie T, Zhao Y, Wu S, Li X, Shi Y. Proc Natl Acad Sci U S A 112 6003-6008 (2015)
  2. Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting. Schützmann MP, Hasecke F, Bachmann S, Zielinski M, Hänsch S, Schröder GF, Zempel H, Hoyer W. Nat Commun 12 4634 (2021)
  3. Rapid automated superposition of shapes and macromolecular models using spherical harmonics. Konarev PV, Petoukhov MV, Svergun DI. J Appl Crystallogr 49 953-960 (2016)
  4. Characterizing the structural ensemble of γ-secretase using a multiscale molecular dynamics approach. Aguayo-Ortiz R, Chávez-García C, Straub JE, Dominguez L. Chem Sci 8 5576-5584 (2017)
  5. Influence of membrane lipid composition on the structure and activity of γ-secretase. Aguayo-Ortiz R, Straub JE, Dominguez L. Phys Chem Chem Phys 20 27294-27304 (2018)
  6. Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations. Kim M, Bezprozvanny I. Int J Mol Sci 22 13600 (2021)
  7. Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis. Feilen LP, Chen SY, Fukumori A, Feederle R, Zacharias M, Steiner H. Elife 11 e76090 (2022)
  8. Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site. Chen SY, Feilen LP, Chávez-Gutiérrez L, Steiner H, Zacharias M. Commun Biol 6 670 (2023)


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  15. Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype. Liu X, Zhao J, Zhang Y, Ubarretxena-Belandia I, Forth S, Lieberman RL, Wang C. Front Mol Neurosci 13 65 (2020)
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