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Structural modeling of calcium binding in the selectivity filter of the L-type calcium channel

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Abstract

Calcium channels play crucial physiological roles. In the absence of high-resolution structures of the channels, the mechanism of ion permeation is unknown. Here we used a method proposed in an accompanying paper (Cheng and Zhorov in Eur Biophys J, 2009) to predict possible chelation patterns of calcium ions in a structural model of the L-type calcium channel. We compared three models in which two or three calcium ions interact with the four selectivity filter glutamates and a conserved aspartate adjacent to the glutamate in repeat II. Monte Carlo energy minimizations yielded many complexes with calcium ions bound to at least two selectivity filter carboxylates. In these complexes calcium-carboxylate attractions are counterbalanced by calcium-calcium and carboxylate-carboxylate repulsions. Superposition of the complexes suggests a high degree of mobility of calcium ions and carboxylate groups of the glutamates. We used the predicted complexes to propose a permeation mechanism that involves single-file movement of calcium ions. The key feature of this mechanism is the presence of bridging glutamates that coordinate two calcium ions and enable their transitions between different chelating patterns involving four to six oxygen atoms from the channel protein. The conserved aspartate is proposed to coordinate a calcium ion incoming to the selectivity filter from the extracellular side. Glutamates in repeats III and IV, which are most distant from the repeat II aspartate, are proposed to coordinate the calcium ion that leaves the selectivity filter to the inner pore. Published experimental data and earlier proposed permeation models are discussed in view of our model.

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Abbreviations

DEKA:

The selectivity filter ring of Asp, Glu, Lys, and Ala residues from the four P-loop repeats of Na+ channels

EEEE:

The ring of glutamates in the selectivity filter of L-type Ca2+ channel

EEEED:

Locus EEEE plus the Asp residue adjacent to the selectivity filter glutamate in repeat II

KvAP:

A bacterial voltage-gated potassium channel

MC:

Monte Carlo

MCM:

Monte Carlo minimization

LTCC:

L-type calcium channel

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Acknowledgments

This study was supported by the CIHR grant MOP-53229 to BSZ. Computations were made possible by the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET: http://www.sharcnet.ca).

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Authors and Affiliations

  1. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada

    Ricky C. K. Cheng, Denis B. Tikhonov & Boris S. Zhorov

  2. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    Denis B. Tikhonov

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  1. Ricky C. K. Cheng
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  2. Denis B. Tikhonov
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  3. Boris S. Zhorov
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Correspondence to Boris S. Zhorov.

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Cheng, R.C.K., Tikhonov, D.B. & Zhorov, B.S. Structural modeling of calcium binding in the selectivity filter of the L-type calcium channel. Eur Biophys J 39, 839–853 (2010). https://doi.org/10.1007/s00249-009-0574-2

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  • DOI: https://doi.org/10.1007/s00249-009-0574-2

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