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 Article · Thu Jan 01 00:00:00 EST 2009 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M109.001842· OSTI ID:980095

Goetz, R; Dover, K; Laezza, F; Shtraizent, N; Huang, X; Tchetchik, D; Eliseenkova, A; Goldfarb, M; Mohammadi, M

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.

• Research Organization: Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: DE-AC02-98CH10886
• OSTI ID: 980095
• Report Number(s): BNL-93013-2010-JA; JBCHA3; TRN: US201015%%1480
• Journal Information: Journal of Biological Chemistry, Vol. 284, Issue 26; ISSN 0021-9258
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
37 INORGANIC
ORGANIC
PHYSICAL AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
CRYSTAL STRUCTURE
CRYSTALS
DATA
FIBROBLASTS
GROWTH FACTORS
HUMAN POPULATIONS
IN VITRO
IN VIVO
INACTIVATION
MODULATION
MUSCLES
MUTAGENESIS
MUTATIONS
NERVE CELLS
NERVES
POTENTIALS
SODIUM
STOWING
SURFACES
national synchrotron light source