Journal of Biological Chemistry
Volume 286, Issue 4, 28 January 2011, Pages 2998-3006
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Membrane Biology
Possible Roles of Exceptionally Conserved Residues around the Selectivity Filters of Sodium and Calcium Channels*

https://doi.org/10.1074/jbc.M110.175406Get rights and content
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In the absence of x-ray structures of sodium and calcium channels their homology models are used to rationalize experimental data and design new experiments. A challenge is to model the outer-pore region that folds differently from potassium channels. Here we report a new model of the outer-pore region of the NaV1.4 channel, which suggests roles of highly conserved residues around the selectivity filter. The model takes from our previous study (Tikhonov, D. B., and Zhorov, B. S. (2005) Biophys. J. 88, 184–197) the general disposition of the P-helices, selectivity filter residues, and the outer carboxylates, but proposes new intra- and inter-domain contacts that support structural stability of the outer pore. Glycine residues downstream from the selectivity filter are proposed to participate in knob-into-hole contacts with the P-helices and S6s. These contacts explain the adapted tetrodotoxin resistance of snakes that feed on toxic prey through valine substitution of isoleucine in the P-helix of repeat IV. Polar residues five positions upstream from the selectivity filter residues form H-bonds with the ascending-limb backbones. Exceptionally conserved tryptophans are engaged in inter-repeat H-bonds to form a ring whose π-electrons would facilitate passage of ions from the outer carboxylates to the selectivity filter. The outer-pore model of CaV1.2 derived from the NaV1.4 model is also stabilized by the ring of exceptionally conservative tryptophans and H-bonds between the P-helices and ascending limbs. In this model, the exceptionally conserved aspartate downstream from the selectivity-filter glutamate in repeat II facilitates passage of calcium ions to the selectivity-filter ring through the tryptophan ring. Available experimental data are discussed in view of the models.

Biophysics
Calcium Channels
Computer Modeling
Ion Channels
Sodium Channels

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*

This study was supported by grants from Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research (MOP-53229) (to B. S. Z.), and by a grant from the RAS Program Molecular and Cell Biology (to D. B. T.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.