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BIOLOGICAL SCIENCES / PHYSIOLOGY
The RCK2 domain of the human BK_Ca channel is a calcium sensor

Taleh Yusifov^*, Nicoletta Savalli^*, Chris S. Gandhi, Michela Ottolia^,, and Riccardo Olcese^*,,¶,||

*Division of Molecular Medicine, Department of Anesthesiology, ^¶Brain Research Institute, Cardiovascular Research Laboratory, and Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7115; and Division of Chemistry and Chemical Engineering, Howard Hughes Medical Institute, MC 114-96, California Institute of Technology, Pasadena, CA 91125

Edited by Ramón Latorre, Centro de Estudios Cientifícos, Valdivia, Chile, and approved November 15, 2007 (received for review June 7, 2007)

Large conductance voltage and Ca²⁺-dependent K⁺ channels (BK_Ca) are activated by both membrane depolarization and intracellular Ca²⁺. Recent studies on bacterial channels have proposed that a Ca²⁺-induced conformational change within specialized regulators of K⁺ conductance (RCK) domains is responsible for channel gating. Each pore-forming subunit of the homotetrameric BK_Ca channel is expected to contain two intracellular RCK domains. The first RCK domain in BK_Ca channels (RCK1) has been shown to contain residues critical for Ca²⁺ sensitivity, possibly participating in the formation of a Ca²⁺-binding site. The location and structure of the second RCK domain in the BK_Ca channel (RCK2) is still being examined, and the presence of a high-affinity Ca²⁺-binding site within this region is not yet established. Here, we present a structure-based alignment of the C terminus of BK_Ca and prokaryotic RCK domains that reveal the location of a second RCK domain in human BK_Ca channels (hSloRCK2). hSloRCK2 includes a high-affinity Ca²⁺-binding site (Ca bowl) and contains similar secondary structural elements as the bacterial RCK domains. Using CD spectroscopy, we provide evidence that hSloRCK2 undergoes a Ca²⁺-induced change in conformation, associated with an -to-β structural transition. We also show that the Ca bowl is an essential element for the Ca²⁺-induced rearrangement of hSloRCK2. We speculate that the molecular rearrangements of RCK2 likely underlie the Ca²⁺-dependent gating mechanism of BK_Ca channels. A structural model of the heterodimeric complex of hSloRCK1 and hSloRCK2 domains is discussed.

BK channel | circular dichroism | MaxiK | RCK | structural modeling

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0705261105/DC1.

^||To whom correspondence should be addressed at: Division of Molecular Medicine, BH 570 CHS, Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA 91195-7115. E-mail: rolcese{at}ucla.edu

© 2008 by The National Academy of Sciences of the USA

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