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Research Papers

Aromaticity at the Water-Hydrocarbon Core Interface of the Membrane: Consequences on the Nicotinic Acetylcholine Receptor

Jose Enrique Lizardi-Ortiz, María C. Hyzinski-García, José E. Fernández-Gerena, Karen M. Osorio-Martínez, Erick Velásquez-Rivera, Félix L. Valle-Avilés and José A. Lasalde-Dominicci

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Almost all lipid-exposed transmembrane domains of integral proteins contain aromatic residues flanking the hydrophobic segment of the domains. These residues generally reside close to the carbonyl region of the membrane, and several structural and functional roles have been associated to these residues. Although the roles and physicochemical reasons for aromatic preference have been extensively studied using model systems, few studies have been done in a native membrane system. To gain insight about the mechanistic implication for this aromatic preference, we selected position αF426 of the muscle-type nicotinic acetylcholine receptor (nAChR). αF426 is a lipid-exposed residue at the extracellular segment of the αM4 transmembrane domain and is highly conserved among different nAChR subunits and species. We used site-directed mutagenesis, α-Bungarotoxin-binding assay, and two-electrodes voltage clamp in Xenopus laevis oocytes to characterize mutations at position αF426, which impart different physicochemical properties like volume, polarity, hydrogen bonds, aromaticity, and net electrical charge. All mutations except the aromatic residues resulted in a significant reduction of the nAChR cell-surface levels and the macroscopic currents to acetylcholine. These results suggest that position αF426 contributes to structural stability and open-close transitions of the nAChR. Finally, the present study also provides information about how intermolecular interactions at position α426 modulate open-close transitions of the nAChR.

Authors

Jose Enrique Lizardi-Ortiz

University of Puerto Rico

María C. Hyzinski-García

University of Puerto Rico

José E. Fernández-Gerena

University of Puerto Rico

Karen M. Osorio-Martínez

Cornell University

Erick Velásquez-Rivera

University of California at Irvine

Félix L. Valle-Avilés

Universidad Central del Caribe

José A. Lasalde-Dominicci

University of Puerto Rico

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