Journal: Nature / Year: 2015 Title: An atomic structure of human γ-secretase. Authors: Xiao-Chen Bai / Chuangye Yan / Guanghui Yang / Peilong Lu / Dan Ma / Linfeng Sun / Rui Zhou / Sjors H W Scheres / Yigong Shi / Abstract: Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1) ...Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.
History
Deposition
Jun 23, 2015
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Header (metadata) release
Jul 1, 2015
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Map release
Aug 12, 2015
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Update
Sep 9, 2015
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Current status
Sep 9, 2015
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
EMPIAR-10194 (Title: An atomic structure of human gamma-secretase / Data size: 11.7 TB Data #1: Unaligned multi-frame micrographs of human gamma-secretase [micrographs - multiframe])
pH: 7.4 Details: 25 mM HEPES, pH 7.4, 150 mM NaCl and amphipol A8-35
Staining
Type: NEGATIVE / Details: cryo-EM
Grid
Details: 300 mesh Au 1.2/1.3 Quantifoil grid, glow discharged for 1 minute
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 85 K / Instrument: FEI VITROBOT MARK IV / Method: Blot for 4 seconds before plunging
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Electron microscopy
Microscope
FEI TITAN KRIOS
Temperature
Min: 80 K / Max: 90 K / Average: 85 K
Specialist optics
Energy filter - Name: Gatan Quantum / Energy filter - Lower energy threshold: 0.0 eV / Energy filter - Upper energy threshold: 20.0 eV
Date
Oct 2, 2014
Image recording
Category: CCD / Film or detector model: GATAN K2 (4k x 4k) / Digitization - Sampling interval: 5 µm / Number real images: 2925 / Average electron dose: 38 e/Å2 Details: 20 frames were recorded by the direct electron detector
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Use a newly developed statistical movie processing and particle polishing approach to compensate for beam-induced movement and reduce the effect of radiation-damage.
CTF correction
Details: Each particle
Final reconstruction
Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: OTHER / Software - Name: CTFFIND3, RELION / Number images used: 159549
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