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Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits

Nature Neuroscience volume 10, pages 32–39 (2007)Cite this article

A Corrigendum to this article was published on 01 February 2007

Abstract

KChIPs coassemble with pore-forming Kv4 α subunits to form a native complex in the brain and heart and regulate the expression and gating properties of Kv4 K+ channels, but the mechanisms underlying these processes are unknown. Here we report a co-crystal structure of the complex of human Kv4.3 N-terminus and KChIP1 at a 3.2-Å resolution. The structure reveals a unique clamping action of the complex, in which a single KChIP1 molecule, as a monomer, laterally clamps two neighboring Kv4.3 N-termini in a 4:4 manner, forming an octamer. The proximal N-terminal peptide of Kv4.3 is sequestered by its binding to an elongated groove on the surface of KChIP1, which is indispensable for the modulation of Kv4.3 by KChIP1, and the same KChIP1 molecule binds to an adjacent T1 domain to stabilize the tetrameric Kv4.3 channels. Taken together with biochemical and functional data, our findings provide a structural basis for the modulation of Kv4 by KChIPs.

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Figure 1: The overall architecture of the KChIP1–Kv4.3N complex.
Figure 2: Significant structural rearrangements occur to KChIP1 upon Kv4.3 N-terminal binding.
Figure 3: The N-terminal inactivation peptide of Kv4.3 is completely sequestered in a hydrophobic groove on the surface of KChIP1.
Figure 4: The second contact interface between KChIP1 and Kv4.3 T1 domain.
Figure 5: Disruption of the second interface by KChIP1 mutation failed to rescue the tetrameric mutant of Kv4.3 C110a mutant that destabilizes tetrameric assembly.
Figure 6: Comparison of the modeled Kv4.3-KChIP1 channel complex with Kv1.2-Kvβ2.

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Acknowledgements

We thank V.J. Karplus for helpful comments on this manuscript and P. Liang for technical support. K.W.W. thanks J. S. Han, Y. Wan and C. Zhou for their support, and specially thanks J. M. Wang for her consistent support and understanding. This work was supported by the '985' grant from the Chinese Ministry of Education and the grant for Project 30630017 by the National Science Foundation of China to K.W.W. and the '863' grant (2003-AA210090) from the Chinese Ministry of Science and Technology to J.J.C. The crystallographic data were collected at the Cornell High Energy Synchrotron Source, which is supported by the National Science Foundation and the National Institute of Health under awards DMR-0225180 and RR01646.

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  1. Huayi Wang and Yan Yan: These authors contributed equally to this work.

Authors and Affiliations

  1. National Institute of Biological Sciences, No. 7 Science Park Road, Beijing, 102206, China

    Huayi Wang, Yue Shen, Linjie Chen & Jijie Chai

  2. Department of Neurobiology, Neuroscience Research Institute, Key Laboratory for Neuroscience of the Ministry of Education, Center for Protein Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100083, China

    Yan Yan, Yanhua Huang, Yi Chen & KeWei Wang

  3. Cornell High-Energy Synchrotron Source, Cornell University, Ithaca, 14853, New York, USA

    Qun Liu, Qiuyue Yang & Quan Hao

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Contributions

H.W. performed the structural biochemistry experiments and Y.Y. conducted the electrophysiology and part of the molecular biology experiments. Q.L., Q.Y. and Q.H. collected the structural data. Y.H, Y.C. and L.C. provided support in for the molecular biology experiments. Y.C. provided electrophysiology support. K.W.W. and J.C. designed and supervised the experiments and wrote the manuscript.

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Correspondence to KeWei Wang or Jijie Chai.

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Wang, H., Yan, Y., Liu, Q. et al. Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits. Nat Neurosci 10, 32–39 (2007). https://doi.org/10.1038/nn1822

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