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Three-dimensional structure of the KChIP1–Kv4.3 T1 complex reveals a cross-shaped octamer

Nature Structural & Molecular Biology volume 13, pages 987995 (2006) | Download Citation

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Abstract

Brain IA and cardiac Ito currents arise from complexes containing Kv4 voltage-gated potassium channels and cytoplasmic calcium-sensor proteins (KChIPs). Here, we present X-ray crystallographic and small-angle X-ray scattering data that show that the KChIP1–Kv4.3 N-terminal cytoplasmic domain complex is a cross-shaped octamer bearing two principal interaction sites. Site 1 comprises interactions between a unique Kv4 channel N-terminal hydrophobic segment and a hydrophobic pocket formed by displacement of the KChIP H10 helix. Site 2 comprises interactions between a T1 assembly domain loop and the KChIP H2 helix. Functional and biochemical studies indicate that site 1 influences channel trafficking, whereas site 2 affects channel gating, and that calcium binding is intimately linked to KChIP folding and complex formation. Together, the data resolve how Kv4 channels and KChIPs interact and provide a framework for understanding how KChIPs modulate Kv4 function.

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Acknowledgements

We thank D. Julius and F. Van Petegem for comments on the manuscript, J. Holton at ALS beamline 8.3.1 for data collection help, L.Y. Jan (University of California San Francisco) for the Kv4.3 clone and Minor laboratory members for support. This work was supported by awards to D.L.M. from the McKnight Foundation for Neuroscience, Rita Allen Foundation, Searle Scholars Award, Arnold and Mabel Beckman Foundation and US National Institutes of Health. G.L.H. was supported by US National Cancer Institute grant CA92584 and US Department of Energy contract DE-AC03-76SF00098. D.L.M. is a McKnight Scholar, Rita Allen Scholar, Searle Scholar and Beckman Young Investigator.

Author information

Author notes

    • Marta Pioletti
    •  & Felix Findeisen

    These authors contributed equally to this work.

Affiliations

  1. Cardiovascular Research Institute, Departments of Biochemistry and Biophysics and Cellular and Molecular Pharmacology, California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 94143-2532, USA.

    • Marta Pioletti
    • , Felix Findeisen
    •  & Daniel L Minor, Jr
  2. Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.

    • Greg L Hura

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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

    Monomer of the KChIP1-T1N fusion, superposition of frequenin EF2 and KChIP1 EF2 and frequenin structure.

  2. 2.

    Supplementary Fig. 2

    T1N helix and linker structure.

  3. 3.

    Supplementary Fig. 3

    Solution analysis of the KChIP1–Kv4.3 T1 complex.

  4. 4.

    Supplementary Fig. 4

    Gel-filtration elution profiles for purified KChIP37–216 and EF mutants.

  5. 5.

    Supplementary Methods

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DOI

https://doi.org/10.1038/nsmb1164

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