title: Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain.
abstract: Voltage-gated calcium channels (Ca(V)s) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration. An essential Ca(V) intracellular protein, the beta-subunit (Ca(V)beta), binds a conserved domain (the alpha-interaction domain, AID) between transmembrane domains I and II of the pore-forming alpha(1) subunit and profoundly affects multiple channel properties such as voltage-dependent activation, inactivation rates, G-protein modulation, drug sensitivity and cell surface expression. Here, we report the high-resolution crystal structures of the Ca(V)beta2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the beta-interaction domain (BID), formed the AID-binding site; however, this region is largely buried in the Ca(V)beta core and is unavailable for protein-protein interactions. The structure of the AID-Ca(V)beta2a complex shows instead that Ca(V)beta2a engages the AID through an extensive, conserved hydrophobic cleft (named the alpha-binding pocket, ABP). The ABP-AID interaction positions one end of the Ca(V)beta near the intracellular end of a pore-lining segment, called IS6, that has a critical role in Ca(V) inactivation. Together, these data suggest that Ca(V)betas influence Ca(V) gating by direct modulation of IS6 movement within the channel pore.
authors.affiliation: Cardiovascular Research Institute, Department of Biochemistry and Biophysics, University of California San Francisco, 513 Parnassus Avenue, Box 0130, San Francisco, California 94143, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Petegem
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Clark
authors.forename: Franck C
authors.initials: FC
authors.lastname: Chatelain
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Minor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism*; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D015220:Calcium Channels; D021122:Protein Subunits