Research Article

Structure of the Human BK Channel Ca2+-Activation Apparatus at 3.0 Å Resolution

Science  09 Jul 2010:
Vol. 329, Issue 5988, pp. 182-186
DOI: 10.1126/science.1190414

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BK Channel Cytoplasmic Domain

BK channels are potassium ion channels found on the surface of a variety of cell types that are essential for the regulation of several key physiological processes, including smooth muscle tone and neuronal excitability. BK channels are regulated by both membrane voltage and intracellular Ca2+. The channel comprises an integral membrane pore, an integral membrane voltage sensor domain, and a large cytoplasmic region that confers Ca2+ sensitivity. Now Yuan et al. (p. 182, published online 27 May; see the Perspective Weyand and Iwata) have determined the crystal structure of the cytoplasmic domain of the human BK channel. Four cytoplasmic regions form a gating ring at the intracellular membrane surface with four Ca2+ binding sites on the outer perimeter.

Abstract

High-conductance voltage- and Ca2+-activated K+ (BK) channels encode negative feedback regulation of membrane voltage and Ca2+ signaling, playing a central role in numerous physiological processes. We determined the x-ray structure of the human BK Ca2+ gating apparatus at a resolution of 3.0 angstroms and deduced its tetrameric assembly by solving a 6 angstrom resolution structure of a Na+-activated homolog. Two tandem C-terminal regulator of K+ conductance (RCK) domains from each of four channel subunits form a 350-kilodalton gating ring at the intracellular membrane surface. A sequence of aspartic amino acids that is known as the Ca2+ bowl, and is located within the second of the tandem RCK domains, creates four Ca2+ binding sites on the outer perimeter of the gating ring at the “assembly interface” between RCK domains. Functionally important mutations cluster near the Ca2+ bowl, near the “flexible interface” between RCK domains, and on the surface of the gating ring that faces the voltage sensors. The structure suggests that the Ca2+ gating ring, in addition to regulating the pore directly, may also modulate the voltage sensor.

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