Structure, dynamics and implied gating mechanism of a human cyclic nucleotide-gated channel. 2014

Yana Gofman, and Charlotta Schärfe, and Debora S Marks, and Turkan Haliloglu, and Nir Ben-Tal
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.

Cyclic nucleotide-gated (CNG) ion channels are nonselective cation channels, essential for visual and olfactory sensory transduction. Although the channels include voltage-sensor domains (VSDs), their conductance is thought to be independent of the membrane potential, and their gating regulated by cytosolic cyclic nucleotide-binding domains. Mutations in these channels result in severe, degenerative retinal diseases, which remain untreatable. The lack of structural information on CNG channels has prevented mechanistic understanding of disease-causing mutations, precluded structure-based drug design, and hampered in silico investigation of the gating mechanism. To address this, we built a 3D model of the cone tetrameric CNG channel, based on homology to two distinct templates with known structures: the transmembrane (TM) domain of a bacterial channel, and the cyclic nucleotide-binding domain of the mouse HCN2 channel. Since the TM-domain template had low sequence-similarity to the TM domains of the CNG channels, and to reconcile conflicts between the two templates, we developed a novel, hybrid approach, combining homology modeling with evolutionary coupling constraints. Next, we used elastic network analysis of the model structure to investigate global motions of the channel and to elucidate its gating mechanism. We found the following: (i) In the main mode of motion, the TM and cytosolic domains counter-rotated around the membrane normal. We related this motion to gating, a proposition that is supported by previous experimental data, and by comparison to the known gating mechanism of the bacterial KirBac channel. (ii) The VSDs could facilitate gating (supplementing the pore gate), explaining their presence in such 'voltage-insensitive' channels. (iii) Our elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently, but are coupled to each other allosterically.

UI MeSH Term Description Entries
D009712 Nucleotides, Cyclic Cyclic Nucleotide,Cyclic Nucleotides,Nucleotide, Cyclic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D017434 Protein Structure, Tertiary The level of protein structure in which combinations of secondary protein structures (ALPHA HELICES; BETA SHEETS; loop regions, and AMINO ACID MOTIFS) pack together to form folded shapes. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Tertiary Protein Structure,Protein Structures, Tertiary,Tertiary Protein Structures
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D054815 Cyclic Nucleotide-Gated Cation Channels A subgroup of cyclic nucleotide-regulated ION CHANNELS within the superfamily of pore-loop cation channels. They are expressed in OLFACTORY NERVE cilia and in PHOTORECEPTOR CELLS and some PLANTS. Cyclic-Nucleotide Gated Ion Channels,CNG Channel (Rod),Cationic Channel Protein (Rod),Cng Cation Channel,Cyclic Nucleotide-Gated Cation Channel,Cyclic-Nucleotide Gated Channel,Cation Channel, Cng,Channel, Cng Cation,Channel, Cyclic-Nucleotide Gated,Cyclic Nucleotide Gated Cation Channel,Cyclic Nucleotide Gated Cation Channels,Cyclic Nucleotide Gated Channel,Cyclic Nucleotide Gated Ion Channels,Gated Channel, Cyclic-Nucleotide
D056004 Molecular Dynamics Simulation A computer simulation developed to study the motion of molecules over a period of time. Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics
D019295 Computational Biology A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories for solving biological problems including manipulation of models and datasets. Bioinformatics,Molecular Biology, Computational,Bio-Informatics,Biology, Computational,Computational Molecular Biology,Bio Informatics,Bio-Informatic,Bioinformatic,Biologies, Computational Molecular,Biology, Computational Molecular,Computational Molecular Biologies,Molecular Biologies, Computational
D064428 Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels A subgroup of cyclic nucleotide-regulated ION CHANNELS of the superfamily of pore-loop cation channels that are opened by hyperpolarization rather than depolarization. The ion conducting pore passes SODIUM, CALCIUM, and POTASSIUM cations with a preference for potassium. Hyperpolarization Cyclic-Nucleotide Gated Ion Channels,HCN Pacemaker Channels,HCN1 Channel,HCN2 Channel,HCN2 Potassium Channel,HCN3 Channel,HCN4 Channel,Hyperpolarization Activated Cyclic Nucleotide-Gated Potassium Channel 2,Hyperpolarization Cyclic-Nucleotide Gated Cation Channel 1,Hyperpolarization Cyclic-Nucleotide Gated Cation Channel 3,Hyperpolarization Cyclic-Nucleotide Gated Cation Channel 4,Hyperpolarization-Activated Cation Channel,I(h) Cation Channels,I(h) Channels,Ih Cation Channels,Potassium-Sodium Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2,Cation Channel, Hyperpolarization-Activated,Cation Channels, Ih,Channel, HCN1,Channel, HCN2,Channel, HCN2 Potassium,Channel, HCN3,Channel, HCN4,Channel, Hyperpolarization-Activated Cation,Channels, HCN Pacemaker,Channels, Ih Cation,Hyperpolarization Activated Cation Channel,Hyperpolarization Activated Cyclic Nucleotide Gated Channels,Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 2,Hyperpolarization Cyclic Nucleotide Gated Cation Channel 1,Hyperpolarization Cyclic Nucleotide Gated Cation Channel 3,Hyperpolarization Cyclic Nucleotide Gated Cation Channel 4,Hyperpolarization Cyclic Nucleotide Gated Ion Channels,Pacemaker Channels, HCN,Potassium Channel, HCN2,Potassium Sodium Hyperpolarization Activated Cyclic Nucleotide Gated Channel 2

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