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Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms1466· OSTI ID:1623877
 [1];  [2];  [2];  [2];  [2]
  1. Univ. of Washington, Seattle, WA (United States). School of Medicine. Howard Hughes Medical Inst. Dept. of Physiology and Biophysics; DOE/OSTI
  2. Univ. of Washington, Seattle, WA (United States). School of Medicine. Howard Hughes Medical Inst. Dept. of Physiology and Biophysics
Molecular determinants of ion channel tetramerization are well characterized, but those involved in heteromeric channel assembly are less clearly understood. The heteromeric composition of native channels is often precisely controlled. Cyclic nucleotide-gated (CNG) channels from rod photoreceptors exhibit a 3:1 stoichiometry of CNGA1 and CNGB1 subunits that tunes the channels for their specialized role in phototransduction. Here we show, using electrophysiology, fluorescence, biochemistry, and X-ray crystallography, that the mechanism for this controlled assembly is the formation of a parallel 3-helix coiled-coil domain of the carboxy-terminal leucine zipper region of CNGA1 subunits, constraining the channel to contain three CNGA1 subunits, followed by preferential incorporation of a single CNGB1 subunit. Deletion of the carboxy-terminal leucine zipper domain relaxed the constraint and permitted multiple CNGB1 subunits in the channel. The X-ray crystal structures of the parallel 3-helix coiled-coil domains of CNGA1 and CNGA3 subunits were similar, suggesting that a similar mechanism controls the stoichiometry of cone CNG channels.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1623877
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 2; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (21)

Isolated rod dysfunction associated with a novel genotype of CNGB1 journal June 2019
Detecting stoichiometry of macromolecular complexes in live cells using FRET journal December 2016
Correction: Corrigendum: Conformational rearrangements in the transmembrane domain of CNGA1 channels revealed by single-molecule force spectroscopy journal September 2017
Deciphering the function of the CNGB1b subunit in olfactory CNG channels journal July 2016
The where and how of PIP regulation of cone photoreceptor CNG channels journal March 2013
Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach journal November 2017
A Cyclic Nucleotide-Gated Channel Mutation Associated with Canine Daylight Blindness Provides Insight into a Role for the S2 Segment Tri-Asp motif in Channel Biogenesis journal February 2014
Whole Exome Analysis Identifies Frequent CNGA1 Mutations in Japanese Population with Autosomal Recessive Retinitis Pigmentosa journal September 2014
Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment journal September 2015
cGMP in mouse rods: the spatiotemporal dynamics underlying single photon responses journal March 2015
Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins journal July 2016
Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy journal March 2018
Molecular Mechanism of TRP Channels book January 2013
Gene therapy for achromatopsia journal March 2017
A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels journal June 2015
Conotoxin κM-RIIIJ, a tool targeting asymmetric heteromeric K v 1 channels journal December 2018
Endoplasmic Reticulum Stress-associated Cone Photoreceptor Degeneration in Cyclic Nucleotide-gated Channel Deficiency journal May 2012
Two structural components in CNGA3 support regulation of cone CNG channels by phosphoinositides journal March 2013
Loss of cone cyclic nucleotide-gated channel leads to alterations in light response modulating system and cellular stress response pathways: a gene expression profiling study journal June 2013
Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy journal October 2018
A Large Animal Model for CNGB1 Autosomal Recessive Retinitis Pigmentosa journal August 2013

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