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The Journal of Neuroscience, November 12, 2003, 23(32):10175-10181
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Cellular/Molecular
The DEP Domain Determines Subcellular Targeting of the GTPase Activating Protein RGS9 In Vivo
Kirill A. Martemyanov,1 Polina V. Lishko,1 Nidia Calero,2 Gabor Keresztes,3 Maxim Sokolov,1 Katherine J. Strissel,1 Ilya B. Leskov,1 Johnathan A. Hopp,1 Alexander V. Kolesnikov,1 Ching-Kang Chen,4 Janis Lem,5 Stefan Heller,3 Marie E. Burns,2 andVadim Y. Arshavsky1 1Howe Laboratory of Ophthalmology, Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, 2Center for Neuroscience and Department of Psychiatry, University of California Davis, Davis, California 95616, 3Department of Otology and Laryngology, Harvard Medical School and Eaton Peabody Laboratory at the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, 4Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah 84112, and 5Molecular Cardiology Research Institute, Department of Ophthalmology, and Program in Genetics, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts 02111
DEP (for Disheveled, EGL-10, Pleckstrin) homology domains are present in numerous signaling proteins, including many in the nervous system, but their function remains mostly elusive. We report that the DEP domain of a photoreceptor-specific signaling protein, RGS9 (for regulator of G-protein signaling 9), plays an essential role in RGS9 delivery to the intracellular compartment of its functioning, the rod outer segment. We generated a transgenic mouse in which RGS9 was replaced by its mutant lacking the DEP domain. We then used a combination of the quantitative technique of serial tangential sectioning-Western blotting with electrophysiological recordings to demonstrate that mutant RGS9 is expressed in rods in the normal amount but is completely excluded from the outer segments. The delivery of RGS9 to rod outer segments is likely to be mediated by the DEP domain interaction with a transmembrane protein, R9AP (for RGS9 anchoring protein), known to anchor RGS9 on the surface of photoreceptor membranes and to potentiate RGS9 catalytic activity. We show that both of these functions are also abolished as the result of the DEP domain deletion. These findings indicate that a novel function of the DEP domain is to target a signaling protein to a specific compartment of a highly polarized neuron. Interestingly, sequence analysis of R9AP reveals the presence of a conserved R-SNARE (for soluble N-ethylmaleimide-sensitive factor attachment protein receptor) motif and a predicted overall structural homology with SNARE proteins involved in vesicular trafficking and fusion. This presents the possibility that DEP domains might serve to target various DEP-containing proteins to the sites of their intracellular action via interactions with the members of extended SNARE protein family.
Key words: DEP domains; RGS proteins; SNARE proteins; protein targeting; photoreceptors; retina
Received Aug 6, 2003; revised September 11, 2003; accepted September 12, 2003.
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