National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)
R01HD061543
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM125629
United States
Citation
Journal: J Biol Chem / Year: 2018 Title: Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating. Authors: Francisco Sierra-Valdez / Caleigh M Azumaya / Luis O Romero / Terunaga Nakagawa / Julio F Cordero-Morales / Abstract: The transient receptor potential ion channels support Ca permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily ...The transient receptor potential ion channels support Ca permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-Å resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.
A: Transient Receptor Potential Cation Channel Subfamily C Member 3 B: Transient Receptor Potential Cation Channel Subfamily C Member 3 C: Transient Receptor Potential Cation Channel Subfamily C Member 3 D: Transient Receptor Potential Cation Channel Subfamily C Member 3
Mass: 41719.434 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
Sequence details
The authors state that the residues could not be assigned at their resolution so all residues are ...The authors state that the residues could not be assigned at their resolution so all residues are modeled as unknown residues. The Short transient receptor potential channel 3 sequence is GAMGSMEGSPSLRRMTVMREKGRRQAVRGPAFMFNDRGTSLTAEEERFLDAAEYGNIPVVRKMLEESKTLNVNCVDYMGQ NALQLAVGNEHLEVTELLLKKENLARIGDALLLAISKGYVRIVEAILNHPGFAASKRLTLSPCEQELQDDDFYAYDEDGT RFSPDITPIILAAHCQKYEVVHMLLMKGARIERPHDYFCKCGDCMEKQRHDSFSHSRSRINAYKGLASPAYLSLSSEDPV LTALELSNELAKLANIEKEFKNDYRKLSMQCKDFVVGVLDLCRDSEEVEAILNGDLESAEPLEVHRHKASLSRVKLAIKY EVKKFVAHPNCQQQLLTIWYENLSGLREQTIAIKCLVVLVVALGLPFLAIGYWIAPCSRLGKILRSPFMKFVAHAASFIV FLGLLVFNASDRFEGITTLPNITVTDYPKQIFRVKTTQFTWTEMLIMVWVLGMMWSECKELWLEGPREYILQLWNVLDFG MLSIFIAAFTARFLAFLQATKAQQYVDSYVQESDLSEVTLPPEIQYFTYARDKWLPSDPQIISEGLYAIAVVLSFSRIAY ILPANESFGPLQISLGRTVKDIFKFMVLFIMVFFAFMIGMFILYSYYLGAKVNAAFTTVEESFKTLFWSIFGLSEVTSVV LKYDHKFIENIGYVLYGIYNVTMVVVLLNMLIAMINSSYQEIEDDSDVEWKFARSKLWLSYFDDGKTLPPPFSLVPSPKS FVYFIMRIVNFPKCRRRRLQKDIEMGMGNSKSRLNLFTQSNSRVFESHSFNSILNQPTRYQQIMKRLIKRYVLKAQVDKE NDEVNEGELKEIKQDISSLRYELLEDKSQATEELAILIHKLSEKLNPSMLRCE
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Experimental details
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Experiment
Experiment
Method: ELECTRON MICROSCOPY
EM experiment
Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction
Model: Tecnai Polara / Image courtesy: FEI Company
Microscopy
Model: FEI POLARA 300
Electron gun
Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lens
Mode: BRIGHT FIELD / Nominal magnification: 31000 X
Specimen holder
Cryogen: NITROGEN
Image recording
Average exposure time: 8 sec. / Electron dose: 100 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 7 / Num. of real images: 5195
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Processing
EM software
ID
Name
Version
Category
2
SerialEM
imageacquisition
4
Gctf
1.06
CTFcorrection
7
Coot
0.8.9
modelfitting
9
PHENIX
1.13-2998
modelrefinement
10
RELION
2.1
initialEulerassignment
11
RELION
2.1
finalEulerassignment
12
RELION
2.1
classification
13
RELION
2.1
3Dreconstruction
CTF correction
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selection
Num. of particles selected: 1410103
Symmetry
Point symmetry: C4 (4 fold cyclic)
3D reconstruction
Resolution: 5.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 56291 / Num. of class averages: 4 / Symmetry type: POINT
Atomic model building
Protocol: AB INITIO MODEL / Space: REAL
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