- PDB-6uiv: Cryo-EM structure of human CALHM2 in an active/open state -
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Basic information
Entry
Database: PDB / ID: 6uiv
Title
Cryo-EM structure of human CALHM2 in an active/open state
Components
Calcium homeostasis modulator protein 2
Keywords
TRANSPORT PROTEIN / calcium homeostasis modulator / CALHM2
Function / homology
Calcium homeostasis modulator family / Calcium homeostasis modulator protein 2 / Calcium homeostasis modulator / ion transport / positive regulation of apoptotic process / integral component of plasma membrane / Calcium homeostasis modulator protein 2
Function and homology information
Biological species
Homo sapiens (human)
Method
ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
Journal: Nature / Year: 2019 Title: The structures and gating mechanism of human calcium homeostasis modulator 2. Authors: Wooyoung Choi / Nicolina Clemente / Weinan Sun / Juan Du / Wei Lü / Abstract: Calcium homeostasis modulators (CALHMs) are voltage-gated, Ca-inhibited nonselective ion channels that act as major ATP release channels, and have important roles in gustatory signalling and neuronal ...Calcium homeostasis modulators (CALHMs) are voltage-gated, Ca-inhibited nonselective ion channels that act as major ATP release channels, and have important roles in gustatory signalling and neuronal toxicity. Dysfunction of CALHMs has previously been linked to neurological disorders. Here we present cryo-electron microscopy structures of the human CALHM2 channel in the Ca-free active or open state and in the ruthenium red (RUR)-bound inhibited state, at resolutions up to 2.7 Å. Our work shows that purified CALHM2 channels form both gap junctions and undecameric hemichannels. The protomer shows a mirrored arrangement of the transmembrane domains (helices S1-S4) relative to other channels with a similar topology, such as connexins, innexins and volume-regulated anion channels. Upon binding to RUR, we observed a contracted pore with notable conformational changes of the pore-lining helix S1, which swings nearly 60° towards the pore axis from a vertical to a lifted position. We propose a two-section gating mechanism in which the S1 helix coarsely adjusts, and the N-terminal helix fine-tunes, the pore size. We identified a RUR-binding site near helix S1 that may stabilize this helix in the lifted conformation, giving rise to channel inhibition. Our work elaborates on the principles of CALHM2 channel architecture and symmetry, and the mechanism that underlies channel inhibition.
Average exposure time: 8 sec. / Electron dose: 54.4 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
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Processing
EM software
ID
Name
Version
Category
1
RELION
3
particleselection
2
SerialEM
3.7
imageacquisition
4
Gctf
CTFcorrection
9
PHENIX
1.16
modelrefinement
10
RELION
3
initialEulerassignment
11
RELION
300
finalEulerassignment
12
RELION
3
classification
13
RELION
3
3Dreconstruction
CTF correction
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selection
Num. of particles selected: 576174
Symmetry
Point symmetry: C11 (11 fold cyclic)
3D reconstruction
Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 84858 / Symmetry type: POINT
Atomic model building
Protocol: AB INITIO MODEL / Space: REAL
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