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.
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 alpha 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.
Goetz
Regina
R
Department of Pharmacology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Dover
Katarzyna
K
Laezza
Fernanda
F
Shtraizent
Nataly
N
Huang
Xiao
X
Tchetchik
Dafna
D
Eliseenkova
Anna V
AV
Xu
Chong-Feng
CF
Neubert
Thomas A
TA
Ornitz
David M
DM
Goldfarb
Mitchell
M
Mohammadi
Moosa
M
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D005346:Fibroblast Growth Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D015222:Sodium Channels; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors