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J. Biol. Chem., Vol. 279, Issue 34, 35932-35941, August 20, 2004

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Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin^*

Aleksandar Stojanovic, Jeremiah Stitham, and John Hwa

From the Departments of Pharmacology & Toxicology and Medicine (Section of Cardiology), Dartmouth Medical School, Hanover, New Hampshire 03755

Zinc deficiency and retinitis pigmentosa are both important factors resulting in retinal dysfunction and night blindness. In this study, we address the critical biochemical and structural relevance of zinc ions in rhodopsin and examine whether zinc deficiency can lead to rhodopsin dysfunction. We report the identification of a high-affinity zinc coordination site within the transmembrane domain of rhodopsin, coordinated by the side chains of two highly conserved residues, Glu¹²² in transmembrane helix III and His²¹¹ in transmembrane helix V. We also demonstrate that this zinc coordination is critical for rhodopsin folding, 11-cis-retinal binding, and the stability of the chromophore-receptor interaction, defects of which are observed in retinitis pigmentosa. Furthermore, a cluster of retinitis pigmentosa mutations is localized within and around this zinc binding site. Based on these studies, we believe that improvement in zinc binding to rhodopsin at this site within the transmembrane domain may be a pharmacological approach for the treatment of select retinitis pigmentosa mutations. Transmembrane coordination of zinc may also be an important common principle across G-protein-coupled receptors.

Received for publication, April 6, 2004 , and in revised form, June 4, 2004.

^* This work was supported in part by grants from the Department of Pharmacology & Toxicology at the Dartmouth Medical School (to J. H.), the Karl Kirchgessner Foundation (to J. H.), a PhRMA Foundation Predoctoral Fellowship (to A. S.), an American Heart Association Predoctoral Fellowship (to J. S.), and by an Albert J. Ryan Foundation Fellowship (to A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

To whom correspondence should be addressed: Dept. of Pharmacology & Toxicology, 7650 Remsen, Dartmouth Medical School, Hanover, NH 03755. Tel.: 603-650-1813; Fax: 603-650-1129; E-mail: John.Hwa{at}Dartmouth.edu.

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