Structural basis for allosteric coupling at the membrane-protein interface in GLIC [Protein Structure and Folding]

December 13th, 2013 by Velisetty, P., Chalamalasetti, S. V., Chakrapani, S.

Ligand-binding at the extracellular domain of pentameric ligand-gated ion channels initiates a relay of conformational changes that culminates at the gate within the transmembrane domain. The interface between the two domains is a key structural entity that governs gating. Molecular events in signal transduction at the interface are poorly defined because of its intrinsically dynamic nature combined with functional modulation by membrane lipid and water-vestibules. Here, we used electron paramagnetic resonance (EPR) spectroscopy to delineate protein motions underlying GLIC gating in a membrane environment and report the interface conformation in the closed and the desensitized states. Extensive intrasubunit interactions were observed in the closed state, which are weakened upon desensitization, and replaced by newer intersubunit contacts. Gating involves major rearrangements of the interfacial loops accompanied by reorganization of the protein-lipid-water interface. These structural changes may serve as targets for modulation of gating by lipids, alcohols, and amphipathic-drug molecules.