The Role of a Voltage-Dependent Ca2+Channel Intracellular Linker: A Structure-Function Analysis
| Autor: | Nathan Dascal, Adva Benmocha, Orna Chomsky-Hecht, Lior Almagor, Joel A. Hirsch, Doran Hendin-Barak |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Microinjections Protein Conformation Protein subunit Molecular Sequence Data Biophysics Regulatory Sequences Nucleic Acid Protein Structure Secondary Membrane Potentials Xenopus laevis Animals Amino Acid Sequence Crystallography Voltage-dependent calcium channel Chemistry Spectrum Analysis General Neuroscience Extracellular Fluid Depolarization Articles Protein Structure Tertiary Transport protein Coupling (electronics) Membrane Biochemistry Mutation Oocytes Calcium Calcium Channels Rabbits Ion Channel Gating Linker Intracellular |
| Zdroj: | The Journal of Neuroscience. 32:7602-7613 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.5727-11.2012 |
| Popis: | Voltage-dependent calcium channels (VDCCs) allow the passage of Ca2+ions through cellular membranes in response to membrane depolarization. The channel pore-forming subunit, α1, and a regulatory subunit (CaVβ) form a high affinity complex where CaVβ binds to a α1 interacting domain in the intracellular linker between α1 membrane domains I and II (I–II linker). We determined crystal structures of CaVβ2 functional core in complex with the CaV1.2 and CaV2.2 I–II linkers to a resolution of 1.95 and 2.0 Å, respectively. Structural differences between the highly conserved linkers, important for coupling CaVβ to the channel pore, guided mechanistic functional studies. Electrophysiological measurements point to the importance of differing linker structure in both CaV1 and 2 subtypes with mutations affecting both voltage- and calcium-dependent inactivation and voltage dependence of activation. These linker effects persist in the absence of CaVβ, pointing to the intrinsic role of the linker in VDCC function and suggesting that I–II linker structure can serve as a brake during inactivation. |
| Databáze: | OpenAIRE |
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