Structure of the gating ring from the human large-conductance Ca 2+-gated K+ channel

Yunkun Wu, Yi Yang, Sheng Ye, Youxing Jiang

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Abstract

Large-conductance Ca2+-gated K+ (BK) channels are essential for many biological processes such as smooth muscle contraction and neurotransmitter release1-4. This group of channels can be activated synergistically by both voltage and intracellular Ca2+, with the large carboxy-terminal intracellular portion being responsible for Ca 2+ sensing5-13. Here we present the crystal structure of the entire cytoplasmic region of the human BK channel in a Ca2+-free state. The structure reveals four intracellular subunits, each comprising two tandem RCK domains, assembled into a gating ring similar to that seen in the MthK channel14 and probably representing its physiological assembly. Three Ca2+ binding sites including the Ca21 bowl are mapped onto the structure based on mutagenesis data. The Ca2+ bowl, located within the secondRCKdomain, forms an EF-hand-like motif and is strategically positioned close to the assembly interface between two subunits. The other two Ca 2+ (or Mg2+) binding sites, Asp 367 and Glu 374/Glu 399, are located on the first RCK domain. The Asp 367 site has high Ca2+ sensitivity and is positioned in the groove between the amino- and carboxyterminal subdomains of RCK+, whereas the low-affinity Mg 2+- binding Glu 374/Glu 399 site is positioned on the upper plateau of the gating ring and close to the membrane. Our structure also contains the linker connecting the transmembrane and intracellulardomains, allowing us to dock a voltage-gatedK1 channel pore of known structure onto the gating ring with reasonable accuracy and generate a structural model for the full BK channel.

Original languageEnglish (US)
Pages (from-to)393-397
Number of pages5
JournalNature
Volume466
Issue number7304
DOIs
StatePublished - Jul 15 2010

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