Abstract
Prestin is the motor protein of cochlear outer hair cells. Its unique capability to perform direct, rapid, and reciprocal electromechanical conversion depends on membrane potential and interaction with intracellular anions. How prestin senses the voltage change and interacts with anions are still unknown. Our three-dimensional model of prestin using molecular dynamics simulations predicts that prestin contains eight transmembrane-spanning segments and two helical re-entry loops and that tyrosyl residues are the structural specialization of the molecule for the unique function of prestin. Using site-directed mutagenesis and electrophysiological techniques, we confirmed that residues Tyr(367), Tyr(486), Tyr(501), and Tyr(508) contribute to anion binding, interacting with intracellular anions through novel anion-π interactions. Such weak interactions, sensitive to voltage and mechanical stimulation, confer prestin with a unique capability to perform electromechanical and mechanoelectric conversions with exquisite sensitivity. This novel mechanism is completely different from all known mechanisms seen in ion channels, transporters, and motor proteins.
Highlights
The structure of the transmembrane domain of prestin and its mechanism of action are unknown
Site-directed Mutagenesis and Electrophysiology—We examined the proposed structure of prestin with site-directed mutagenesis and electrophysiological measurement from HEK cells transfected with different sets of mutant prestin
On the basis of molecular dynamics (MD) simulations, sitedirected mutagenesis, and electrophysiological measurements, we propose a novel mechanism for the unique voltage-dependent function of prestin
Summary
The structure of the transmembrane domain of prestin and its mechanism of action are unknown. Using site-directed mutagenesis and electrophysiological techniques, we confirmed that residues Tyr367, Tyr486, Tyr501, and Tyr508 contribute to anion binding, interacting with intracellular anions through novel anion- interactions Such weak interactions, sensitive to voltage and mechanical stimulation, confer prestin with a unique capability to perform electromechanical and mechanoelectric conversions with exquisite sensitivity. Sensitive to voltage and mechanical stimulation, confer prestin with a unique capability to perform electromechanical and mechanoelectric conversions with exquisite sensitivity This novel mechanism is completely different from all known mechanisms seen in ion channels, transporters, and motor proteins. Prestin can respond to voltage change (signified by the presence of a gating current) and undergo conformational change (reflected by length change of outer hair cells) Such voltage-dependent properties lie in distinct regions within the SulTP domain (residues 70 –512) [11,12,13,14]. The non-covalent anion- interactions [25,26,27,28] of anions with the aromatic rings of Tyr367, Tyr486, Tyr501, and Tyr508 furnish prestin with a unique capability to bind to anions and respond to voltage and mechanical stimulations
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