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Essential Cavβ modulatory properties are AID-independent

Nature Structural & Molecular Biology volume 12, pages 372–377 (2005)Cite this article

Abstract

Voltage-gated Ca2+ channel β (Cavβ) subunits have a highly conserved core consisting of interacting Src homology 3 and guanylate kinase domains, and are postulated to exert their effects through AID, the major interaction site in the pore-forming α1 subunit. This stereotypical interaction does not explain how individual Cavβ subunits modulate α1 subunits differentially. Here we show that AID is neither necessary nor sufficient for critical Cavβ regulatory properties. Complete modulation depends on additional contacts that are exclusive of AID and not revealed in recent crystal structures. These data offer a new context for understanding Cavβ modulation, suggesting that the AID interaction orients the Cavβ core so as to permit additional isoform-specific Cavα1-Cavβ interactions that underlie the particular regulation seen with each Cavα1-Cavβ pair, rather than as the main site of regulation.

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Figure 1: Schematic of Cavα1 and β subunits.
Figure 2: The SH3 module contributes to Cavβ modulation.
Figure 3: The SH3 module binds to the α1 I-II intracellular linker.
Figure 4: Functionally important Cavβ modulation requires Cavα1-Cavβ contacts outside of the AID.
Figure 5: Deletion in the Cav1.2 I-II loop affects inactivation and blocks SH3 interaction.

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Acknowledgements

This work was supported by the US National Institutes of Health and the Irma T. Hirschl Trust (G.S.P.). We thank J. Riley and S. Siegelbaum for supplying Xenopus oocytes.

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Author notes

  1. Janet M Maltez and Deborah A Nunziato: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Columbia University, New York, 10032, New York, USA

    Janet M Maltez, Deborah A Nunziato, James Kim & Geoffrey S Pitt

  2. Department of Medicine (Cardiology), Columbia University, New York, 10032, New York, USA

    Geoffrey S Pitt

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  1. Janet M Maltez
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Correspondence to Geoffrey S Pitt.

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Maltez, J., Nunziato, D., Kim, J. et al. Essential Cavβ modulatory properties are AID-independent. Nat Struct Mol Biol 12, 372–377 (2005). https://doi.org/10.1038/nsmb909

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