PDBsum entry 1vyv

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protein Protein-protein interface(s) links
Transport protein PDB id
Protein chains
275 a.a. *
* Residue conservation analysis
PDB id:
Name: Transport protein
Title: Beta4 subunit of ca2+ channel
Structure: Calcium channel beta-4subunit. Chain: a, b. Engineered: yes
Source: Rattus norvegicus. Rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 469008.
3Å     R-factor:   0.248     R-free:   0.287
Authors: Y.-H.Chen,M.-H.Li,Y.Zhang,L.-L.He,Y.Yamada,A.Fitzmaurice, S.Yang,H.Zhang,T.Liang,J.Yang
Key ref:
Y.H.Chen et al. (2004). Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels. Nature, 429, 675-680. PubMed id: 15170217 DOI: 10.1038/nature02641
07-May-04     Release date:   15-Jun-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
D4A055  (D4A055_RAT) -  Calcium channel, voltage-dependent, beta 4 subunit, isoform CRA_b
486 a.a.
275 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     voltage-gated calcium channel complex   1 term 
  Biological process     calcium ion transmembrane transport   1 term 
  Biochemical function     voltage-gated calcium channel activity     1 term  


DOI no: 10.1038/nature02641 Nature 429:675-680 (2004)
PubMed id: 15170217  
Structural basis of the alpha1-beta subunit interaction of voltage-gated Ca2+ channels.
Y.H.Chen, M.H.Li, Y.Zhang, L.L.He, Y.Yamada, A.Fitzmaurice, Y.Shen, H.Zhang, L.Tong, J.Yang.
High-voltage-activated Ca2+ channels are essential for diverse biological processes. They are composed of four or five subunits, including alpha1, alpha2-delta, beta and gamma (ref. 1). Their expression and function are critically dependent on the beta-subunit, which transports alpha1 to the surface membrane and regulates diverse channel properties. It is believed that the beta-subunit interacts with alpha1 primarily through the beta-interaction domain (BID), which binds directly to the alpha-interaction domain (AID) of alpha1; however, the molecular mechanism of the alpha1-beta interaction is largely unclear. Here we report the crystal structures of the conserved core region of beta3, alone and in complex with AID, and of beta4 alone. The structures show that the beta-subunit core contains two interacting domains: a Src homology 3 (SH3) domain and a guanylate kinase (GK) domain. The AID binds to a hydrophobic groove in the GK domain through extensive interactions, conferring extremely high affinity between alpha1 and beta-subunits. The BID is essential both for the structural integrity of and for bridging the SH3 and GK domains, but it does not participate directly in binding alpha1. The presence of multiple protein-interacting modules in the beta-subunit opens a new dimension to its function as a multi-functional protein.
  Selected figure(s)  
Figure 2.
Figure 2: Crystal structure of the beta-[3] core in complex with its alpha-[1] binding partner (AID). The [3] core can be divided into three regions: an SH3 domain (residues 60 -120 and 170 -175, gold), a HOOK region (residues 121 -169, purple) and a GK domain (residues 176 -360, green). Residues 226 -244 (forming the 4 helix) are disordered in this molecule but are well resolved in another one in the same asymmetric unit. Residues 422 -446 of Ca[V]1.2c containing the entire AID are coloured in orange. This and all subsequent ribbon diagrams were generated with the program RIBBONS28.
Figure 4.
Figure 4: Structural comparisons of the beta--subunit core. a, Superposition of the apo- [3] core (red) and [3] core -AID complex (black). This and all subsequent trace diagrams were produced with the program Molscript30. b, Close-up of the AID-binding site of apo- [3] core (magenta) and [3] core -AID complex (green). c, Superposition of [3] core (red) and [4] core (black). In a and c, only the GK domains were superimposed. Stereo views of a and c are in Supplementary Fig. 1.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2004, 429, 675-680) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21186355 C.Altier, A.Garcia-Caballero, B.Simms, H.You, L.Chen, J.Walcher, H.W.Tedford, T.Hermosilla, and G.W.Zamponi (2011).
The CavĪ² subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels.
  Nat Neurosci, 14, 173-180.  
20451250 A.Dayal, J.Schredelseker, C.Franzini-Armstrong, and M.Grabner (2010).
Skeletal muscle excitation-contraction coupling is independent of a conserved heptad repeat motif in the C-terminus of the DHPRbeta(1a) subunit.
  Cell Calcium, 47, 500-506.  
19996312 G.J.Obermair, B.Schlick, V.Di Biase, P.Subramanyam, M.Gebhart, S.Baumgartner, and B.E.Flucher (2010).
Reciprocal interactions regulate targeting of calcium channel beta subunits and membrane expression of alpha1 subunits in cultured hippocampal neurons.
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  20142517 M.R.Tadross, M.Ben Johny, and D.T.Yue (2010).
Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels.
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19821165 W.Jangsangthong, E.Kuzmenkina, I.F.Khan, J.Matthes, R.Hullin, and S.Herzig (2010).
Inactivation of L-type calcium channels is determined by the length of the N terminus of mutant beta(1) subunits.
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19917615 Y.Zhang, Y.Yamada, M.Fan, S.D.Bangaru, B.Lin, and J.Yang (2010).
The beta subunit of voltage-gated Ca2+ channels interacts with and regulates the activity of a novel isoform of Pax6.
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18651169 A.V.Dresviannikov, K.M.Page, J.Leroy, W.S.Pratt, and A.C.Dolphin (2009).
Determinants of the voltage dependence of G protein modulation within calcium channel beta subunits.
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19492014 E.Kobrinsky, P.Abrahimi, S.Q.Duong, S.Thomas, J.B.Harry, C.Patel, Q.Z.Lao, and N.M.Soldatov (2009).
Effect of Ca(v)beta subunits on structural organization of Ca(v)1.2 calcium channels.
  PLoS One, 4, e5587.  
  19237593 F.Findeisen, and D.L.Minor (2009).
Disruption of the IS6-AID linker affects voltage-gated calcium channel inactivation and facilitation.
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19038263 F.Potet, C.I.Petersen, O.Boutaud, W.Shuai, S.Z.Stepanovic, J.R.Balser, and S.Kupershmidt (2009).
Genetic screening in C. elegans identifies rho-GTPase activating protein 6 as novel HERG regulator.
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19663902 J.R.Taylor, Z.Zheng, Z.M.Wang, A.M.Payne, M.L.Messi, and O.Delbono (2009).
Increased CaVbeta1A expression with aging contributes to skeletal muscle weakness.
  Aging Cell, 8, 584-594.  
  19342611 S.Dai, D.D.Hall, and J.W.Hell (2009).
Supramolecular assemblies and localized regulation of voltage-gated ion channels.
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19673672 S.Telemaque, and J.D.Marsh (2009).
Modification of cardiovascular ion channels by gene therapy.
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  19858358 T.Mitra-Ganguli, I.Vitko, E.Perez-Reyes, and A.R.Rittenhouse (2009).
Orientation of palmitoylated CaVbeta2a relative to CaV2.2 is critical for slow pathway modulation of N-type Ca2+ current by tachykinin receptor activation.
  J Gen Physiol, 134, 385-396.  
19554083 T.Nogi, D.Zhang, J.D.Chan, and J.S.Marchant (2009).
A novel biological activity of praziquantel requiring voltage-operated ca channel Beta subunits: subversion of flatworm regenerative polarity.
  PLoS Negl Trop Dis, 3, e464.  
19153575 W.Feng, and M.Zhang (2009).
Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density.
  Nat Rev Neurosci, 10, 87-99.  
19675352 X.Xu, and H.M.Colecraft (2009).
Engineering proteins for custom inhibition of Ca(V) channels.
  Physiology (Bethesda), 24, 210-218.  
19427861 Y.H.Chen, L.L.He, D.R.Buchanan, Y.Zhang, A.Fitzmaurice, and J.Yang (2009).
Functional dissection of the intramolecular Src homology 3-guanylate kinase domain coupling in voltage-gated Ca2+ channel beta-subunits.
  FEBS Lett, 583, 1969-1975.  
18172207 A.M.Ebert, C.A.McAnelly, A.Srinivasan, J.L.Linker, W.A.Horne, and D.M.Garrity (2008).
Ca2+ channel-independent requirement for MAGUK family CACNB4 genes in initiation of zebrafish epiboly.
  Proc Natl Acad Sci U S A, 105, 198-203.  
18419826 A.M.Ebert, C.A.McAnelly, A.Srinivasan, R.L.Mueller, D.B.Garrity, and D.M.Garrity (2008).
The calcium channel beta2 (CACNB2) subunit repertoire in teleosts.
  BMC Mol Biol, 9, 38.  
18682574 A.M.Ebert, C.A.McAnelly, A.V.Handschy, R.L.Mueller, W.A.Horne, and D.M.Garrity (2008).
Genomic organization, expression, and phylogenetic analysis of Ca2+ channel beta4 genes in 13 vertebrate species.
  Physiol Genomics, 35, 133-144.  
18535142 A.Ravindran, Q.Z.Lao, J.B.Harry, P.Abrahimi, E.Kobrinsky, and N.M.Soldatov (2008).
Calmodulin-dependent gating of Ca(v)1.2 calcium channels in the absence of Ca(v)beta subunits.
  Proc Natl Acad Sci U S A, 105, 8154-8159.  
18339621 D.Jeon, I.Song, W.Guido, K.Kim, E.Kim, U.Oh, and H.S.Shin (2008).
Ablation of Ca2+ channel beta3 subunit leads to enhanced N-methyl-D-aspartate receptor-dependent long term potentiation and improved long term memory.
  J Biol Chem, 283, 12093-12101.  
18275819 F.Van Petegem, K.E.Duderstadt, K.A.Clark, M.Wang, and D.L.Minor (2008).
Alanine-scanning mutagenesis defines a conserved energetic hotspot in the CaValpha1 AID-CaVbeta interaction site that is critical for channel modulation.
  Structure, 16, 280-294.  
  18725532 G.Gonzalez-Gutierrez, E.Miranda-Laferte, D.Naranjo, P.Hidalgo, and A.Neely (2008).
Mutations of nonconserved residues within the calcium channel alpha1-interaction domain inhibit beta-subunit potentiation.
  J Gen Physiol, 132, 383-395.  
18776052 G.Gonzalez-Gutierrez, E.Miranda-Laferte, D.Nothmann, S.Schmidt, A.Neely, and P.Hidalgo (2008).
The guanylate kinase domain of the beta-subunit of voltage-gated calcium channels suffices to modulate gating.
  Proc Natl Acad Sci U S A, 105, 14198-14203.  
18958281 I.Vitko, A.Shcheglovitov, J.P.Baumgart, I.I.Arias-Olguín, J.Murbartián, J.M.Arias, and E.Perez-Reyes (2008).
Orientation of the calcium channel beta relative to the alpha(1)2.2 subunit is critical for its regulation of channel activity.
  PLoS ONE, 3, e3560.  
  18596857 J.D.Marsh, S.Telemaque, S.W.Rhee, J.R.Stimers, and N.J.Rusch (2008).
Delivery of ion channel genes to treat cardiovascular diseases.
  Trans Am Clin Climatol Assoc, 119, 171.  
18509027 K.Yu, Q.Xiao, G.Cui, A.Lee, and H.C.Hartzell (2008).
The best disease-linked Cl- channel hBest1 regulates Ca V 1 (L-type) Ca2+ channels via src-homology-binding domains.
  J Neurosci, 28, 5660-5670.  
18628210 M.Murakami, T.Ohba, F.Xu, E.Satoh, I.Miyoshi, T.Suzuki, Y.Takahashi, E.Takahashi, H.Watanabe, K.Ono, H.Sasano, N.Kasai, H.Ito, and T.Iijima (2008).
Modified Sympathetic Nerve System Activity with Overexpression of the Voltage-dependent Calcium Channel {beta}3 Subunit.
  J Biol Chem, 283, 24554-24560.  
17924144 P.Y.Cho, T.I.Kim, S.M.Whang, and S.J.Hong (2008).
Gene expression profile of Clonorchis sinensis metacercariae.
  Parasitol Res, 102, 277-282.  
18411278 Q.Z.Lao, E.Kobrinsky, J.B.Harry, A.Ravindran, and N.M.Soldatov (2008).
New Determinant for the CaVbeta2 subunit modulation of the CaV1.2 calcium channel.
  J Biol Chem, 283, 15577-15588.  
18556650 R.A.Bannister, M.Grabner, and K.G.Beam (2008).
The {alpha}1S III-IV Loop Influences 1,4-Dihydropyridine Receptor Gating but Is Not Directly Involved in Excitation-Contraction Coupling Interactions with the Type 1 Ryanodine Receptor.
  J Biol Chem, 283, 23217-23223.  
18042346 R.N.Correll, C.Pang, D.M.Niedowicz, B.S.Finlin, and D.A.Andres (2008).
The RGK family of GTP-binding proteins: regulators of voltage-dependent calcium channels and cytoskeleton remodeling.
  Cell Signal, 20, 292-300.  
18068949 R.N.Correll, G.J.Botzet, J.Satin, D.A.Andres, and B.S.Finlin (2008).
Analysis of the Rem2 - voltage dependant calcium channel beta subunit interaction and Rem2 interaction with phosphorylated phosphatidylinositide lipids.
  Cell Signal, 20, 400-408.  
19109500 Y.Zhang, Y.H.Chen, S.D.Bangaru, L.He, K.Abele, S.Tanabe, T.Kozasa, and J.Yang (2008).
Origin of the voltage dependence of G-protein regulation of P/Q-type Ca2+ channels.
  J Neurosci, 28, 14176-14188.  
17521566 D.L.Minor (2007).
The neurobiologist's guide to structural biology: a primer on why macromolecular structure matters and how to evaluate structural data.
  Neuron, 54, 511-533.  
17110381 G.Gonzalez-Gutierrez, E.Miranda-Laferte, A.Neely, and P.Hidalgo (2007).
The Src homology 3 domain of the beta-subunit of voltage-gated calcium channels promotes endocytosis via dynamin interaction.
  J Biol Chem, 282, 2156-2162.  
18001290 K.S.Richards, A.M.Swensen, D.Lipscombe, and K.Bommert (2007).
Novel CaV2.1 clone replicates many properties of Purkinje cell CaV2.1 current.
  Eur J Neurosci, 26, 2950-2961.  
17496037 L.L.He, Y.Zhang, Y.H.Chen, Y.Yamada, and J.Yang (2007).
Functional modularity of the beta-subunit of voltage-gated Ca2+ channels.
  Biophys J, 93, 834-845.  
17664337 M.Xie, X.Li, J.Han, D.L.Vogt, S.Wittemann, M.D.Mark, and S.Herlitze (2007).
Facilitation versus depression in cultured hippocampal neurons determined by targeting of Ca2+ channel Cavbeta4 versus Cavbeta2 subunits to synaptic terminals.
  J Cell Biol, 178, 489-502.  
17303572 P.Béguin, Y.J.Ng, C.Krause, R.N.Mahalakshmi, M.Y.Ng, and W.Hunziker (2007).
RGK small GTP-binding proteins interact with the nucleotide kinase domain of Ca2+-channel beta-subunits via an uncommon effector binding domain.
  J Biol Chem, 282, 11509-11520.  
17899404 R.A.Bannister (2007).
Bridging the myoplasmic gap: recent developments in skeletal muscle excitation-contraction coupling.
  J Muscle Res Cell Motil, 28, 275-283.  
17028169 A.Badou, M.K.Jha, D.Matza, W.Z.Mehal, M.Freichel, V.Flockerzi, and R.A.Flavell (2006).
Critical role for the beta regulatory subunits of Cav channels in T lymphocyte function.
  Proc Natl Acad Sci U S A, 103, 15529-15534.  
16402121 A.C.Dolphin (2006).
A short history of voltage-gated calcium channels.
  Br J Pharmacol, 147, S56-S62.  
16385006 A.C.Vendel, C.D.Rithner, B.A.Lyons, and W.A.Horne (2006).
Solution structure of the N-terminal A domain of the human voltage-gated Ca2+channel beta4a subunit.
  Protein Sci, 15, 378-383.
PDB code: 2d46
16627564 A.J.Butcher, J.Leroy, M.W.Richards, W.S.Pratt, and A.C.Dolphin (2006).
The importance of occupancy rather than affinity of CaV(beta) subunits for the calcium channel I-II linker in relation to calcium channel function.
  J Physiol, 574, 387-398.  
16706839 A.Sandoval, N.Oviedo, A.Tadmouri, T.Avila, M.De Waard, and R.Felix (2006).
Two PEST-like motifs regulate Ca2+/calpain-mediated cleavage of the CaVbeta3 subunit and provide important determinants for neuronal Ca2+ channel activity.
  Eur J Neurosci, 23, 2311-2320.  
16790445 B.S.Finlin, R.N.Correll, C.Pang, S.M.Crump, J.Satin, and D.A.Andres (2006).
Analysis of the complex between Ca2+ channel beta-subunit and the Rem GTPase.
  J Biol Chem, 281, 23557-23566.  
17052221 F.Van Petegem, and D.L.Minor (2006).
The structural biology of voltage-gated calcium channel function and regulation.
  Biochem Soc Trans, 34, 887-893.  
  16801381 N.Kanevsky, and N.Dascal (2006).
Regulation of maximal open probability is a separable function of Ca(v)beta subunit in L-type Ca2+ channel, dependent on NH2 terminus of alpha1C (Ca(v)1.2alpha).
  J Gen Physiol, 128, 15-36.  
16317008 V.Leuranguer, S.Papadopoulos, and K.G.Beam (2006).
Organization of calcium channel beta1a subunits in triad junctions in skeletal muscle.
  J Biol Chem, 281, 3521-3527.  
16982421 Y.Li, Y.Wu, and Y.Zhou (2006).
Modulation of inactivation properties of CaV2.2 channels by 14-3-3 proteins.
  Neuron, 51, 755-771.  
15953418 H.L.Agler, J.Evans, L.H.Tay, M.J.Anderson, H.M.Colecraft, and D.T.Yue (2005).
G protein-gated inhibitory module of N-type (ca(v)2.2) ca2+ channels.
  Neuron, 46, 891-904.  
16322774 I.Bodi, G.Mikala, S.E.Koch, S.A.Akhter, and A.Schwartz (2005).
The L-type calcium channel in the heart: the beat goes on.
  J Clin Invest, 115, 3306-3317.  
15750602 J.M.Maltez, D.A.Nunziato, J.Kim, and G.S.Pitt (2005).
Essential Ca(V)beta modulatory properties are AID-independent.
  Nat Struct Mol Biol, 12, 372-377.  
15507442 L.Berrou, Y.Dodier, A.Raybaud, A.Tousignant, O.Dafi, J.N.Pelletier, and L.Parent (2005).
The C-terminal residues in the alpha-interacting domain (AID) helix anchor CaV beta subunit interaction and modulation of CaV2.3 channels.
  J Biol Chem, 280, 494-505.  
15816172 R.J.French, and G.W.Zamponi (2005).
Voltage-gated sodium and calcium channels in nerve, muscle, and heart.
  IEEE Trans Nanobioscience, 4, 58-69.  
  16569296 R.M.Greenberg (2005).
Ca2+ signalling, voltage-gated Ca2+ channels and praziquantel in flatworm neuromusculature.
  Parasitology, 131, S97-108.  
16020456 S.Dalton, S.X.Takahashi, J.Miriyala, and H.M.Colecraft (2005).
A single CaVbeta can reconstitute both trafficking and macroscopic conductance of voltage-dependent calcium channels.
  J Physiol, 567, 757-769.  
  16186563 S.X.Takahashi, J.Miriyala, L.H.Tay, D.T.Yue, and H.M.Colecraft (2005).
A CaVbeta SH3/guanylate kinase domain interaction regulates multiple properties of voltage-gated Ca2+ channels.
  J Gen Physiol, 126, 365-377.  
15627376 I.I.Serysheva (2004).
Structural insights into excitation-contraction coupling by electron cryomicroscopy.
  Biochemistry (Mosc), 69, 1226-1232.  
15339916 J.B.Harry, E.Kobrinsky, D.R.Abernethy, and N.M.Soldatov (2004).
New short splice variants of the human cardiac Cavbeta2 subunit: redefining the major functional motifs implemented in modulation of the Cav1.2 channel.
  J Biol Chem, 279, 46367-46372.  
15265869 J.D.Spafford, J.Van Minnen, P.Larsen, A.B.Smit, N.I.Syed, and G.W.Zamponi (2004).
Uncoupling of calcium channel alpha1 and beta subunits in developing neurons.
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15530640 M.W.Richards, A.J.Butcher, and A.C.Dolphin (2004).
Ca2+ channel beta-subunits: structural insights AID our understanding.
  Trends Pharmacol Sci, 25, 626-632.  
15339810 O.Dafi, L.Berrou, Y.Dodier, A.Raybaud, R.Sauvé, and L.Parent (2004).
Negatively charged residues in the N-terminal of the AID helix confer slow voltage dependent inactivation gating to CaV1.2.
  Biophys J, 87, 3181-3192.  
15479643 P.O.Berggren, S.N.Yang, M.Murakami, A.M.Efanov, S.Uhles, M.Köhler, T.Moede, A.Fernström, I.B.Appelskog, C.A.Aspinwall, S.V.Zaitsev, O.Larsson, Vargas, C.Fecher-Trost, P.Weissgerber, A.Ludwig, B.Leibiger, L.Juntti-Berggren, C.J.Barker, J.Gromada, M.Freichel, I.B.Leibiger, and V.Flockerzi (2004).
Removal of Ca2+ channel beta3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis.
  Cell, 119, 273-284.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.