Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels

Regina Goetz, Katarzyna Dover, Fernanda Laezza, Nataly Shtraizent, Xiao Huang, Dafna Tchetchik, Anna V. Eliseenkova, Chong Feng Xu, Thomas A. Neubert, David M. Ornitz, Mitchell Goldfarb, Moosa Mohammadi

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Voltage-gated sodium channels (Nav) produce sodium currents that underlie the initiation and propagation of action potentials in nerve and muscle cells. Fibroblast growth factor homologous factors (FHFs) bind to the intracellular C-terminal region of the Nav α subunit to modulate fast inactivation of the channel. In this study we solved the crystal structure of a 149-residue-long fragment of human FHF2A which unveils the structural features of the homology core domain of all 10 human FHF isoforms. Through analysis of crystal packing contacts and site-directed mutagenesis experiments we identified a conserved surface on the FHF core domain that mediates channel binding in vitro and in vivo. Mutations at this channel binding surface impaired the ability of FHFs to co-localize with Navs at the axon initial segment of hippocampal neurons. The mutations also disabled FHF modulation of voltage-dependent fast inactivation of sodium channels in neuronal cells. Based on our data, we propose that FHFs constitute auxiliary subunits for Navs.

Original languageEnglish (US)
Pages (from-to)17883-17896
Number of pages14
JournalJournal of Biological Chemistry
Volume284
Issue number26
DOIs
StatePublished - Jun 26 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Goetz, R., Dover, K., Laezza, F., Shtraizent, N., Huang, X., Tchetchik, D., Eliseenkova, A. V., Xu, C. F., Neubert, T. A., Ornitz, D. M., Goldfarb, M., & Mohammadi, M. (2009). Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels. Journal of Biological Chemistry, 284(26), 17883-17896. https://doi.org/10.1074/jbc.M109.001842