Advanced search

Crystallographic insights into sodium-channel modulation by the β4 subunit

Author
Organization
Abstract
Voltage-gated sodium (Na-v) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, beta-subunits modify Na-v channel function and cause debilitating disorders when mutated. While investigating whether beta-subunits also influence ligand interactions, we found that beta 4 dramatically alters toxin binding to Na(v)1.2. To explore these observations further, we solved the crystal structure of the extracellular beta 4 domain and identified (58)Cys as an exposed residue that, when mutated, eliminates the influence of beta 4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of beta 4. Disrupting this bridge by introducing a beta 1 mutation implicated in epilepsy repositions the (58)Cys-containing loop and disrupts beta 4 modulation of Na(v)1.2. Overall, the principles emerging from this work (i) help explain tissuedependent variations in Nav channel pharmacology; (ii) enable the mechanistic interpretation of beta-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant beta-subunit behavior.
Keywords
voltage-gated sodium channel, beta4 subunit, ProTx-II, X-ray structure, disease mutations, GATED NA+ CHANNELS, RAT-BRAIN, MOLECULAR DETERMINANTS, FEBRILE SEIZURES, SCORPION TOXIN, ALPHA-SUBUNIT, FUNCTIONAL EXPRESSION, NEURITIC DEGENERATION, GENERALIZED EPILEPSY, EXTRACELLULAR DOMAIN

Citation

Please use this url to cite or link to this publication:

Chicago
Gilchrist, John, Samir Das, Filip Van Petegem, and Frank Bosmans. 2013. “Crystallographic Insights into Sodium-channel Modulation by the Β4 Subunit.” Proceedings of the National Academy of Sciences of the United States of America 110 (51): E5016–E5024.
APA
Gilchrist, John, Das, S., Van Petegem, F., & Bosmans, F. (2013). Crystallographic insights into sodium-channel modulation by the β4 subunit. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(51), E5016–E5024.
Vancouver
1.
Gilchrist J, Das S, Van Petegem F, Bosmans F. Crystallographic insights into sodium-channel modulation by the β4 subunit. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2013;110(51):E5016–E5024.
MLA
Gilchrist, John, Samir Das, Filip Van Petegem, et al. “Crystallographic Insights into Sodium-channel Modulation by the Β4 Subunit.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110.51 (2013): E5016–E5024. Print.
@article{8584526,
  abstract     = {Voltage-gated sodium (Na-v) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, beta-subunits modify Na-v channel function and cause debilitating disorders when mutated. While investigating whether beta-subunits also influence ligand interactions, we found that beta 4 dramatically alters toxin binding to Na(v)1.2. To explore these observations further, we solved the crystal structure of the extracellular beta 4 domain and identified (58)Cys as an exposed residue that, when mutated, eliminates the influence of beta 4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of beta 4. Disrupting this bridge by introducing a beta 1 mutation implicated in epilepsy repositions the (58)Cys-containing loop and disrupts beta 4 modulation of Na(v)1.2. Overall, the principles emerging from this work (i) help explain tissuedependent variations in Nav channel pharmacology; (ii) enable the mechanistic interpretation of beta-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant beta-subunit behavior.},
  author       = {Gilchrist, John and Das, Samir and Van Petegem, Filip and Bosmans, Frank},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  language     = {eng},
  number       = {51},
  pages        = {E5016--E5024},
  title        = {Crystallographic insights into sodium-channel modulation by the \ensuremath{\beta}4 subunit},
  url          = {http://dx.doi.org/10.1073/pnas.1314557110},
  volume       = {110},
  year         = {2013},
}

Altmetric
View in Altmetric
Web of Science
Times cited: