Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 329 (5988): 182-186

Copyright © 2010 by the American Association for the Advancement of Science

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

Peng Yuan, Manuel D. Leonetti, Alexander R. Pico,* Yichun Hsiung, Roderick MacKinnon{dagger}

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.

Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.

* Present address: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.

{dagger} To whom correspondence should be addressed. E-mail: mackinn{at}

Structure and Function of TMEM16 Proteins (Anoctamins).
N. Pedemonte and L. J. V. Galietta (2014)
Physiol Rev 94, 419-459
   Abstract »    Full Text »    PDF »
Mitochondrial Channels: Ion Fluxes and More.
I. Szabo and M. Zoratti (2014)
Physiol Rev 94, 519-608
   Abstract »    Full Text »    PDF »
Properties of Slo1 K+ channels with and without the gating ring.
G. Budelli, Y. Geng, A. Butler, K. L. Magleby, and L. Salkoff (2013)
PNAS 110, 16657-16662
   Abstract »    Full Text »    PDF »
The Interface between Membrane-Spanning and Cytosolic Domains in Ca2+-Dependent K+ Channels Is Involved in {beta} Subunit Modulation of Gating.
X. Sun, J. Shi, K. Delaloye, X. Yang, H. Yang, G. Zhang, and J. Cui (2013)
J. Neurosci. 33, 11253-11261
   Abstract »    Full Text »    PDF »
Transduction of Voltage and Ca2+ Signals by Slo1 BK Channels.
T. Hoshi, A. Pantazis, and R. Olcese (2013)
Physiology 28, 172-189
   Abstract »    Full Text »    PDF »
Specific phosphorylation sites underlie the stimulation of a large conductance, Ca2+-activated K+ channel by cGMP-dependent protein kinase.
B. D. Kyle, S. Hurst, R. D. Swayze, J. Sheng, and A. P. Braun (2013)
FASEB J 27, 2027-2038
   Abstract »    Full Text »    PDF »
Ligand-Gating by Ca2+ Is Rate Limiting for Physiological Operation of BKCa Channels.
H. Berkefeld and B. Fakler (2013)
J. Neurosci. 33, 7358-7367
   Abstract »    Full Text »    PDF »
State-dependent FRET reports calcium- and voltage-dependent gating-ring motions in BK channels.
P. Miranda, J. E. Contreras, A. J. R. Plested, F. J. Sigworth, M. Holmgren, and T. Giraldez (2013)
PNAS 110, 5217-5222
   Abstract »    Full Text »    PDF »
Regulation of Ion Channels by Pyridine Nucleotides.
P. J. Kilfoil, S. M. Tipparaju, O. A. Barski, and A. Bhatnagar (2013)
Circ. Res. 112, 721-741
   Abstract »    Full Text »    PDF »
Interaction between residues in the Mg2+-binding site regulates BK channel activation.
J. Yang, H. Yang, X. Sun, K. Delaloye, X. Yang, A. Moller, J. Shi, and J. Cui (2013)
J. Gen. Physiol. 141, 217-228
   Abstract »    Full Text »    PDF »
Slo1 is the principal potassium channel of human spermatozoa.
N. Mannowetz, N. M. Naidoo, S.-A. S. Choo, J. F. Smith, and P. V. Lishko (2013)
eLife Sci 2, e01009
   Abstract »    Full Text »    PDF »
A linkage analysis toolkit for studying allosteric networks in ion channels.
D. Sigg (2012)
J. Gen. Physiol. 141, 29-60
   Abstract »    Full Text »    PDF »
Intracellular BKCa (iBKCa) channels.
H. Singh, E. Stefani, and L. Toro (2012)
J. Physiol. 590, 5937-5947
   Abstract »    Full Text »    PDF »
Perspectives on: Conformational coupling in ion channels: Conformational coupling in BK potassium channels.
F. T. Horrigan (2012)
J. Gen. Physiol. 140, 625-634
   Abstract »    Full Text »    PDF »
Functional and structural analysis of the human SLO3 pH- and voltage-gated K+ channel.
M. D. Leonetti, P. Yuan, Y. Hsiung, and R. MacKinnon (2012)
PNAS 109, 19274-19279
   Abstract »    Full Text »    PDF »
Relative transmembrane segment rearrangements during BK channel activation resolved by structurally assigned fluorophore-quencher pairing.
A. Pantazis and R. Olcese (2012)
J. Gen. Physiol. 140, 207-218
   Abstract »    Full Text »    PDF »
Barium ions selectively activate BK channels via the Ca2+-bowl site.
Y. Zhou, X.-H. Zeng, and C. J. Lingle (2012)
PNAS 109, 11413-11418
   Abstract »    Full Text »    PDF »
The Contribution of RCK Domains to Human BK Channel Allosteric Activation.
N. Savalli, A. Pantazis, T. Yusifov, D. Sigg, and R. Olcese (2012)
J. Biol. Chem. 287, 21741-21750
   Abstract »    Full Text »    PDF »
Multiple Cholesterol Recognition/Interaction Amino Acid Consensus (CRAC) Motifs in Cytosolic C Tail of Slo1 Subunit Determine Cholesterol Sensitivity of Ca2+- and Voltage-gated K+ (BK) Channels.
A. K. Singh, J. McMillan, A. N. Bukiya, B. Burton, A. L. Parrill, and A. M. Dopico (2012)
J. Biol. Chem. 287, 20509-20521
   Abstract »    Full Text »    PDF »
C-terminal Acidic Cluster Is Involved in Ca2+-induced Regulation of Human Transient Receptor Potential Ankyrin 1 Channel.
L. Sura, V. Zima, L. Marsakova, A. Hynkova, I. Barvik, and V. Vlachova (2012)
J. Biol. Chem. 287, 18067-18077
   Abstract »    Full Text »    PDF »
Cell Excitability Necessary for Male Mating Behavior in Caenorhabditis elegans Is Coordinated by Interactions Between Big Current and Ether-A-Go-Go Family K+ Channels.
B. LeBoeuf and L. R. Garcia (2012)
Genetics 190, 1025-1041
   Abstract »    Full Text »    PDF »
Molecular mechanism of pharmacological activation of BK channels.
G. Gessner, Y.-M. Cui, Y. Otani, T. Ohwada, M. Soom, T. Hoshi, and S. H. Heinemann (2012)
PNAS 109, 3552-3557
   Abstract »    Full Text »    PDF »
An Electrostatic Switch Controls Palmitoylation of the Large Conductance Voltage- and Calcium-activated Potassium (BK) Channel.
O. Jeffries, L. Tian, H. McClafferty, and M. J. Shipston (2012)
J. Biol. Chem. 287, 1468-1477
   Abstract »    Full Text »    PDF »
Distinct gating mechanisms revealed by the structures of a multi-ligand gated K+ channel.
C. Kong, W. Zeng, S. Ye, L. Chen, D. B. Sauer, Y. Lam, M. G. Derebe, and Y. Jiang (2012)
eLife Sci 1, e00184
   Abstract »    Full Text »    PDF »
Alternatively spliced domains interact to regulate BK potassium channel gating.
B. E. Johnson, D. A. Glauser, E. S. Dan-Glauser, D. B. Halling, R. W. Aldrich, and M. B. Goodman (2011)
PNAS 108, 20784-20789
   Abstract »    Full Text »    PDF »
Mg2+ binding to open and closed states can activate BK channels provided that the voltage sensors are elevated.
R.-S. Chen, Y. Geng, and K. L. Magleby (2011)
J. Gen. Physiol. 138, 593-607
   Abstract »    Full Text »    PDF »
LRRC52 (leucine-rich-repeat-containing protein 52), a testis-specific auxiliary subunit of the alkalization-activated Slo3 channel.
C. Yang, X.-H. Zeng, Y. Zhou, X.-M. Xia, and C. J. Lingle (2011)
PNAS 108, 19419-19424
   Abstract »    Full Text »    PDF »
Charge substitution for a deep-pore residue reveals structural dynamics during BK channel gating.
X. Chen and R. W. Aldrich (2011)
J. Gen. Physiol. 138, 137-154
   Abstract »    Full Text »    PDF »
Where's the gate? Gating in the deep pore of the BKCa channel.
D. H. Cox and T. Hoshi (2011)
J. Gen. Physiol. 138, 133-136
   Full Text »    PDF »
Mechanism of activation gating in the full-length KcsA K+ channel.
S. Uysal, L. G. Cuello, D. M. Cortes, S. Koide, A. A. Kossiakoff, and E. Perozo (2011)
PNAS 108, 11896-11899
   Abstract »    Full Text »    PDF »
Metal-driven Operation of the Human Large-conductance Voltage- and Ca2+-dependent Potassium Channel (BK) Gating Ring Apparatus.
A. D. Javaherian, T. Yusifov, A. Pantazis, S. Franklin, C. S. Gandhi, and R. Olcese (2011)
J. Biol. Chem. 286, 20701-20709
   Abstract »    Full Text »    PDF »
Interaction between IP3 receptors and BK channels in arterial smooth muscle: non-canonical IP3 signaling at work.
P. E. Mujica and F. G. Gonzalez (2011)
J. Gen. Physiol. 137, 473-477
   Full Text »    PDF »
A Novel Auxiliary Subunit Critical to BK Channel Function in Caenorhabditis elegans.
B. Chen, Q. Ge, X.-M. Xia, P. Liu, S. J. Wang, H. Zhan, B. A. Eipper, and Z.-W. Wang (2010)
J. Neurosci. 30, 16651-16661
   Abstract »    Full Text »    PDF »
Relative motion of transmembrane segments S0 and S4 during voltage sensor activation in the human BKCa channel.
A. Pantazis, A. P. Kohanteb, and R. Olcese (2010)
J. Gen. Physiol. 136, 645-657
   Abstract »    Full Text »    PDF »
Modulation of BK Channel Gating by the {beta}2 Subunit Involves Both Membrane-Spanning and Cytoplasmic Domains of Slo1.
U. S. Lee, J. Shi, and J. Cui (2010)
J. Neurosci. 30, 16170-16179
   Abstract »    Full Text »    PDF »
BK-type calcium-activated potassium channels: coupling of metal ions and voltage sensing.
J. Cui (2010)
J. Physiol. 588, 4651-4658
   Abstract »    Full Text »    PDF »
Inhibition of Large-Conductance Ca2+-Activated K+ Channels by Nanomolar Concentrations of Ag+.
Y. Zhou, X. Xia, and C. J. Lingle (2010)
Mol. Pharmacol. 78, 952-960
   Abstract »    Full Text »    PDF »
Ion sensing in the RCK1 domain of BK channels.
G. Zhang, S.-Y. Huang, J. Yang, J. Shi, X. Yang, A. Moller, X. Zou, and J. Cui (2010)
PNAS 107, 18700-18705
   Abstract »    Full Text »    PDF »
{alpha}-Catulin CTN-1 is required for BK channel subcellular localization in C. elegans body-wall muscle cells.
B. Chen, P. Liu, S. J. Wang, Q. Ge, H. Zhan, W. A. Mohler, and Z.-W. Wang (2010)
EMBO J. 29, 3184-3195
   Abstract »    Full Text »    PDF »
Allosteric interactions and the modular nature of the voltage- and Ca2+-activated (BK) channel.
R. Latorre, F. J. Morera, and C. Zaelzer (2010)
J. Physiol. 588, 3141-3148
   Abstract »    Full Text »    PDF »
Old Gate Gets a New Look.
S. Weyand and S. Iwata (2010)
Science 329, 151-152
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882