Publication: Possible roles of exceptionally conserved residues around the selectivity filters of sodium and calcium channels
All || By Area || By Year| Title | Possible roles of exceptionally conserved residues around the selectivity filters of sodium and calcium channels | Authors/Editors* | Tikhonov DB, Zhorov BS |
|---|---|
| Where published* | J Biol Chem |
| How published* | Journal |
| Year* | 2011 |
| Volume | 286 |
| Number | 4 |
| Pages | 2998-3006 |
| Publisher | |
| Keywords | |
| Link | http://www.ncbi.nlm.nih.gov/pubmed/21081490 |
| Abstract |
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 & Zhorov. 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, which 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 pi-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. |
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