A Structural Model for Prestin and Related SLC26 Anion Transporters

Abstract

Mammalian hearing relies on active mechanical amplification of sound in the cochlea, which requires process termed electromotility, i.e. voltage-driven ultrafast length changes of sensory outer hair cells (OHC). The electromotility is generated by prestin (solute carrier transmembrane protein SLC26A5), an anion transporter-related, OHC-specific membrane protein. Electromechanical activity of prestin results from conformational changes that are directly triggered by changes in membrane potential and involve interaction with anions. These conformational changes are tightly coupled to substantial intramembraneous charge movement providing prestin with a unique electrical signature that can be measured as a non-linear membrane capacitance (NLC). The molecular mechanisms underlying prestin's electromotile function and anion translocation by SLC26 transporters are essentially unknown. While direct structural information on this protein family is sill lacking, different protein structures were previously suggested based on bioinformatical and mutagenesis studies. We addressed this issue by performing an extensive topological study by substituted cysteine accessibility method (SCAM). Our results indicate a structure different from those proposed earlier. Moreover, by homology modeling we succeed to establish a structural model that is in agreement with extensive experimental data and provide general insights into the molecular mechanisms of SLC26 transporters.