Three-dimensional structure of CaV3.1: comparison with the cardiac L-type voltage-gated calcium channel monomer architecture.
Calcium entry through voltage-gated calcium channels has widespread cellular effects upon a host of physiological processes including neuronal excitability, muscle excitation-contraction coupling, and secretion. Using single particle analysis methods, we have determined the first three-dimensional structure, at 23 A resolution, for a member of the low voltage-activated voltage-gated calcium channel family, CaV3.1, a T-type channel. CaV3.1 has dimensions of approximately 115x85x95 A, composed of two distinct segments. The cytoplasmic densities form a vestibule below the transmembrane domain with the C terminus, unambiguously identified by the presence of a His tag being approximately 65 A long and curling around the base of the structure. The cytoplasmic assembly has a large exposed surface area that may serve as a signaling hub with the C terminus acting as a "fishing rod" to bind regulatory proteins. We have also determined a three-dimensional structure, at a resolution of 25 A, for the monomeric form of the cardiac L-type voltage-gated calcium (high voltage-activated) channel with accessory proteins beta and alpha2delta bound to the ion channel polypeptide CaV1.2. Comparison with the skeletal muscle isoform finds a good match particularly with respect to the conformation, size, and shape of the domain identified as that formed by alpha2. Furthermore, modeling of the CaV3.1 structure (analogous to CaV1.2 at these resolutions) into the heteromeric L-type voltage-gated calcium channel complex volume reveals multiple interaction sites for beta-CaV1.2 binding and for the first time identifies the size and organization of the alpha2delta polypeptides.
Walsh
Conor P
CP
Cardiovascular Medicine, School of Clinical and Laboratory Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9NT.
Davies
Anthony
A
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Butcher
Adrian J
AJ
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Dolphin
Annette C
AC
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Kitmitto
Ashraf
A
Cardiovascular Medicine, School of Clinical and Laboratory Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9NT.
D000818:Animals; D020746:Calcium Channels, L-Type / Q000737:chemistry*; D020747:Calcium Channels, T-Type / Q000737:chemistry*; D002417:Cattle; D018360:Crystallography, X-Ray / Q000379:methods; D003593:Cytoplasm / Q000378:metabolism; D006321:Heart / Q000502:physiology; D007313:Insecta; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats
C500994:Cacna1g protein, rat; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D010455:Peptides; D020033:Protein Isoforms