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Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex

Nature Structural & Molecular Biology volume 12, pages 11081115 (2005) | Download Citation

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Abstract

Changes in activity-dependent calcium flux through voltage-gated calcium channels (CaVs) drive two self-regulatory calcium-dependent feedback processes that require interaction between Ca2+/calmodulin (Ca2+/CaM) and a CaV channel consensus isoleucine-glutamine (IQ) motif: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). Here, we report the high-resolution structure of the Ca2+/CaM–CaV1.2 IQ domain complex. The IQ domain engages hydrophobic pockets in the N-terminal and C-terminal Ca2+/CaM lobes through sets of conserved 'aromatic anchors.' Ca2+/N lobe adopts two conformations that suggest inherent conformational plasticity at the Ca2+/N lobe–IQ domain interface. Titration calorimetry experiments reveal competition between the lobes for IQ domain sites. Electrophysiological examination of Ca2+/N lobe aromatic anchors uncovers their role in CaV1.2 CDF. Together, our data suggest that CaV subtype differences in CDI and CDF are tuned by changes in IQ domain anchoring positions and establish a framework for understanding CaM lobe–specific regulation of CaVs.

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Acknowledgements

We thank K. Brejc and D. Fass for comments on the manuscript; J. Holton at Beamline 8.3.1 at the Advanced Light Source for help with data collection; C.B. Klee (US National Institutes of Health, Bethesda, Maryland, USA) for the calmodulin clone; R.W. Tsien (Stanford University School of Medicine, Stanford, California, USA) and D.T. Yue (Johns Hopkins University School of Medicine, Baltimore, USA) for calcium channel clones; and members of the Minor laboratory for support at all stages of this work. This work was supported by awards to D.L.M. from the McKnight Foundation for Neuroscience, the Rita Allen Foundation, the Alfred P. Sloan Foundation and the US National Institutes of Health and to F.V.P. from the American Heart Association Western States Affiliate. D.L.M. is a McKnight Scholar in Neurosciences, an Alfred P. Sloan Research Fellow and a Rita Allen Foundation Scholar.

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  1. Cardiovascular Research Institute, Department of Biochemistry and Biophysics and Department of Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research, University of California, San Francisco, 1700 4th St., Box 2532, San Francisco, California 94143-2532, USA.

    • Filip Van Petegem
    • , Franck C Chatelain
    •  & Daniel L Minor, Jr

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel L Minor, Jr.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Experimentally phased and density modified electron density map for the IQ domain in complex A.

  2. 2.

    Supplementary Fig. 2

    Details of interactions of Cav1.2 IQ domain residues with Ca2+/CaM.

  3. 3.

    Supplementary Fig. 3

    Overview of main chain and side chain interactions in complexes A and C.

  4. 4.

    Supplementary Fig. 4

    Sequence alignment of the IQ domains of Cav1, Cav2 and Nav1 channels.

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https://doi.org/10.1038/nsmb1027

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