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The Journal of Neuroscience, December 6, 2006, 26(49):12727-12734; doi:10.1523/JNEUROSCI.2734-06.2006

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Cellular/Molecular
Essential Helix Interactions in the Anion Transporter Domain of Prestin Revealed by Evolutionary Trace Analysis

Lavanya Rajagopalan,¹ Nimish Patel,^2 * Srinivasan Madabushi,^3 * Julie Anne Goddard,^2 * Venkat Anjan,² Feng Lin,⁴ Cindy Shope,² Brenda Farrell,² Olivier Lichtarge,³ Amy L. Davidson,¹ William E. Brownell,² and Fred A. Pereira^2,4

¹Department of Molecular Virology, ²Bobby R. Alford Department of Otolaryngology–Head and Neck Surgery, ³Department of Molecular and Human Genetics, and ⁴Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Fred A. Pereira, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Email: fpereira{at}bcm.edu

Prestin, a member of the SLC26A family of anion transporters, is a polytopic membrane protein found in outer hair cells (OHCs) of the mammalian cochlea. Prestin is an essential component of the membrane-based motor that enhances electromotility of OHCs and contributes to frequency sensitivity and selectivity in mammalian hearing. Mammalian cells expressing prestin display a nonlinear capacitance (NLC), widely accepted as the electrical signature of electromotility. The associated charge movement requires intracellular anions reflecting the membership of prestin in the SLC26A family. We used the computational approach of evolutionary trace analysis to identify candidate functional (trace) residues in prestin for mutational studies. We created a panel of mutations at each trace residue and determined membrane expression and nonlinear capacitance associated with each mutant. We observe that several residue substitutions near the conserved sulfate transporter domain of prestin either greatly reduce or eliminate NLC, and the effect is dependent on the size of the substituted residue. These data suggest that packing of helices and interactions between residues surrounding the "sulfate transporter motif" is essential for normal prestin activity.

Key words: prestin; OHC; electromotility; nonlinear capacitance; evolutionary trace; auditory

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Received April 17, 2006; revised Oct. 24, 2006; accepted Oct. 25, 2006.

Correspondence should be addressed to Fred A. Pereira, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Email: fpereira{at}bcm.edu

This article has been cited by other articles:

				J. Sfondouris, L. Rajagopalan, F. A. Pereira, and W. E. Brownell Membrane Composition Modulates Prestin-associated Charge Movement J. Biol. Chem., August 15, 2008; 283(33): 22473 - 22481. [Abstract] [Full Text] [PDF]

				J. Ashmore Cochlear Outer Hair Cell Motility Physiol Rev, January 1, 2008; 88(1): 173 - 210. [Abstract] [Full Text] [PDF]

				L. Rajagopalan, J. N. Greeson, A. Xia, H. Liu, A. Sturm, R. M. Raphael, A. L. Davidson, J. S. Oghalai, F. A. Pereira, and W. E. Brownell Tuning of the Outer Hair Cell Motor by Membrane Cholesterol J. Biol. Chem., December 14, 2007; 282(50): 36659 - 36670. [Abstract] [Full Text] [PDF]

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