title: Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels.
abstract: The gating of pentameric ligand-gated ion channels is sensitive to a variety of allosteric modulators that act on structures peripheral to those involved in the allosteric pathway leading from the agonist site to the channel gate. One such structure, the lipid-exposed transmembrane α helix, M4, is the target of lipids, neurosteroids, and disease-causing mutations. Here we show that M4 interactions with the adjacent transmembrane α helices, M1 and M3, modulate pLGIC function. Enhanced M4 interactions promote channel function while ineffective interactions reduce channel function. The interface chemistry governs the intrinsic strength of M4-M1/M3 inter-helical interactions, both influencing channel gating and imparting distinct susceptibilities to the potentiating effects of a lipid-facing M4 congenital myasthenic syndrome mutation. Through aromatic substitutions, functional studies, and molecular dynamics simulations, we elucidate a mechanism by which M4 modulates channel function.
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Casey L
authors.initials: CL
authors.lastname: Carswell
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Camille M
authors.initials: CM
authors.lastname: Hénault
authors.affiliation: Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, NJ 08102, USA.
authors.forename: Sruthi
authors.initials: S
authors.lastname: Murlidaran
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: J P Daniel
authors.initials: JPD
authors.lastname: Therien
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Juranka
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Surujballi
authors.affiliation: Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, NJ 08102, USA; Department of Physics, Rutgers University-Camden, Camden, NJ 08103, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Brannigan
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada. Electronic address: john.baenziger@uottawa.ca.
authors.forename: John E
authors.initials: JE
authors.lastname: Baenziger
mesh_terms: D000494:Allosteric Regulation; D006801:Humans; D058446:Ligand-Gated Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D058446:Ligand-Gated Ion Channels