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. 2002 Mar;82(3):1207–1215. doi: 10.1016/S0006-3495(02)75477-5

Molecular modeling and dynamics of the sodium channel inactivation gate.

Fernanda L Sirota 1, Pedro G Pascutti 1, Celia Anteneodo 1
PMCID: PMC1301924  PMID: 11867438

Abstract

The intracellular linker L(III-IV) of voltage-gated sodium channels is known to be involved in their mechanism of inactivation. Its primary sequence is well conserved in sodium channels from different tissues and species. However, the role of charged residues in this region, first thought to play an important role in inactivation, has not been well identified, whereas the IFM triad (I1488-M1490) has been characterized as the crucial element for inactivation. In this work, we constructed theoretical models and performed molecular dynamics simulations, exploring the role of L(III-IV)-charged residues in the presence of a polar/nonpolar planar interface represented by a dielectric discontinuity. From structural predictions, two alpha-helical segments are proposed. Moreover, from dynamics simulations, a time-conserved motif is detected and shown to play a relevant role in guiding the inactivation particle toward its receptor site.

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Selected References

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  1. Berman H. M., Westbrook J., Feng Z., Gilliland G., Bhat T. N., Weissig H., Shindyalov I. N., Bourne P. E. The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235–242. doi: 10.1093/nar/28.1.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bower M. J., Cohen F. E., Dunbrack R. L., Jr Prediction of protein side-chain rotamers from a backbone-dependent rotamer library: a new homology modeling tool. J Mol Biol. 1997 Apr 18;267(5):1268–1282. doi: 10.1006/jmbi.1997.0926. [DOI] [PubMed] [Google Scholar]
  3. Catterall W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000 Apr;26(1):13–25. doi: 10.1016/s0896-6273(00)81133-2. [DOI] [PubMed] [Google Scholar]
  4. Dunbrack R. L., Jr, Cohen F. E. Bayesian statistical analysis of protein side-chain rotamer preferences. Protein Sci. 1997 Aug;6(8):1661–1681. doi: 10.1002/pro.5560060807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dunbrack R. L., Jr, Karplus M. Backbone-dependent rotamer library for proteins. Application to side-chain prediction. J Mol Biol. 1993 Mar 20;230(2):543–574. doi: 10.1006/jmbi.1993.1170. [DOI] [PubMed] [Google Scholar]
  6. Dunbrack R. L., Jr, Karplus M. Conformational analysis of the backbone-dependent rotamer preferences of protein sidechains. Nat Struct Biol. 1994 May;1(5):334–340. doi: 10.1038/nsb0594-334. [DOI] [PubMed] [Google Scholar]
  7. Kellenberger S., West J. W., Catterall W. A., Scheuer T. Molecular analysis of potential hinge residues in the inactivation gate of brain type IIA Na+ channels. J Gen Physiol. 1997 May;109(5):607–617. doi: 10.1085/jgp.109.5.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kelley L. A., MacCallum R. M., Sternberg M. J. Enhanced genome annotation using structural profiles in the program 3D-PSSM. J Mol Biol. 2000 Jun 2;299(2):499–520. doi: 10.1006/jmbi.2000.3741. [DOI] [PubMed] [Google Scholar]
  9. Kneller D. G., Cohen F. E., Langridge R. Improvements in protein secondary structure prediction by an enhanced neural network. J Mol Biol. 1990 Jul 5;214(1):171–182. doi: 10.1016/0022-2836(90)90154-E. [DOI] [PubMed] [Google Scholar]
  10. Miller J. R., Patel M. K., John J. E., Mounsey J. P., Moorman J. R. Contributions of charged residues in a cytoplasmic linking region to Na channel gating. Biochim Biophys Acta. 2000 Dec 20;1509(1-2):275–291. doi: 10.1016/s0005-2736(00)00304-7. [DOI] [PubMed] [Google Scholar]
  11. Moorman J. R., Kirsch G. E., Brown A. M., Joho R. H. Changes in sodium channel gating produced by point mutations in a cytoplasmic linker. Science. 1990 Nov 2;250(4981):688–691. doi: 10.1126/science.2173138. [DOI] [PubMed] [Google Scholar]
  12. Noda M., Ikeda T., Kayano T., Suzuki H., Takeshima H., Kurasaki M., Takahashi H., Numa S. Existence of distinct sodium channel messenger RNAs in rat brain. Nature. 1986 Mar 13;320(6058):188–192. doi: 10.1038/320188a0. [DOI] [PubMed] [Google Scholar]
  13. Oh D., Shin S. Y., Lee S., Kang J. H., Kim S. D., Ryu P. D., Hahm K. S., Kim Y. Role of the hinge region and the tryptophan residue in the synthetic antimicrobial peptides, cecropin A(1-8)-magainin 2(1-12) and its analogues, on their antibiotic activities and structures. Biochemistry. 2000 Oct 3;39(39):11855–11864. doi: 10.1021/bi000453g. [DOI] [PubMed] [Google Scholar]
  14. Pascutti P. G., El-Jaik L. J., Bisch P. M., Mundim K. C., Ito A. S. Molecular dynamics simulation of alpha-melanocyte stimulating hormone in a water-membrane model interface. Eur Biophys J. 1999;28(6):499–509. doi: 10.1007/s002490050232. [DOI] [PubMed] [Google Scholar]
  15. Patton D. E., West J. W., Catterall W. A., Goldin A. L. Amino acid residues required for fast Na(+)-channel inactivation: charge neutralizations and deletions in the III-IV linker. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10905–10909. doi: 10.1073/pnas.89.22.10905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Perozo E., Bezanilla F. Phosphorylation affects voltage gating of the delayed rectifier K+ channel by electrostatic interactions. Neuron. 1990 Nov;5(5):685–690. doi: 10.1016/0896-6273(90)90222-2. [DOI] [PubMed] [Google Scholar]
  17. Rohl C. A., Boeckman F. A., Baker C., Scheuer T., Catterall W. A., Klevit R. E. Solution structure of the sodium channel inactivation gate. Biochemistry. 1999 Jan 19;38(3):855–861. doi: 10.1021/bi9823380. [DOI] [PubMed] [Google Scholar]
  18. Rooman M. J., Kocher J. P., Wodak S. J. Prediction of protein backbone conformation based on seven structure assignments. Influence of local interactions. J Mol Biol. 1991 Oct 5;221(3):961–979. doi: 10.1016/0022-2836(91)80186-x. [DOI] [PubMed] [Google Scholar]
  19. Sato C., Ueno Y., Asai K., Takahashi K., Sato M., Engel A., Fujiyoshi Y. The voltage-sensitive sodium channel is a bell-shaped molecule with several cavities. Nature. 2001 Feb 22;409(6823):1047–1051. doi: 10.1038/35059098. [DOI] [PubMed] [Google Scholar]
  20. Stühmer W., Conti F., Suzuki H., Wang X. D., Noda M., Yahagi N., Kubo H., Numa S. Structural parts involved in activation and inactivation of the sodium channel. Nature. 1989 Jun 22;339(6226):597–603. doi: 10.1038/339597a0. [DOI] [PubMed] [Google Scholar]
  21. West J. W., Numann R., Murphy B. J., Scheuer T., Catterall W. A. A phosphorylation site in the Na+ channel required for modulation by protein kinase C. Science. 1991 Nov 8;254(5033):866–868. doi: 10.1126/science.1658937. [DOI] [PubMed] [Google Scholar]
  22. West J. W., Patton D. E., Scheuer T., Wang Y., Goldin A. L., Catterall W. A. A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10910–10914. doi: 10.1073/pnas.89.22.10910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wintjens R. T., Rooman M. J., Wodak S. J. Automatic classification and analysis of alpha alpha-turn motifs in proteins. J Mol Biol. 1996 Jan 12;255(1):235–253. doi: 10.1006/jmbi.1996.0020. [DOI] [PubMed] [Google Scholar]

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