Abstract
The assembly of signalling molecules into macromolecular complexes (transducisomes) provides specificity, sensitivity and speed in intracellular signalling pathways1,2. Rod photoreceptors in the eye contain an unusual set of glutamic-acid-rich proteins (GARPs) of unknown function3,4,5,6,7. GARPs exist as two soluble forms, GARP1 and GARP2, and as a large cytoplasmic domain (GARP′ part) of the β-subunit of the cyclic GMP-gated channel3,4,5,6,7. Here we identify GARPs as multivalent proteins that interact with the keyplayers of cGMP signalling, phosphodiesterase and guanylate cyclase, and with a retina-specific ATP-binding cassette transporter (ABCR)8,9, through four, short, repetitive sequences. In electron micrographs, GARPs are restricted to the rim region and incisures of discs in close proximity to the guanylate cyclase and ABCR, whereas the phosphodiesterase is randomly distributed. GARP2, the most abundant splice form, associates more strongly with light-activated than with inactive phosphodiesterase, and GARP2 potently inhibits phosphodiesterase activity. Thus, the GARPs organize a dynamic protein complex near the disc rim that may control cGMP turnover and possibly other light-dependent processes. Because there are no similar GARPs in cones, we propose that GARPs may prevent unnecessary cGMP turnover during daylight, when rods are held in saturation by the relatively high light levels.
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Acknowledgements
We thank J. Beavo, J. Nathans, I. Weyand and D. Weitz for antibodies, A. Eckert forpreparing the manuscript, I. Weyand and R. Seifert for critical reading of the manuscript, and E. Pugh and R. Cote for discussions. This work was supported by grants from the EU (U.B.K.), the Deutsche Forschungsgemeinschaft (M.B., K.P.H., K.-W.K., U.B.K., U.W.) and the FAUN-Stiftung (U.W.).
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Körschen, H., Beyermann, M., Müller, F. et al. Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors. Nature 400, 761–766 (1999). https://doi.org/10.1038/23468
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DOI: https://doi.org/10.1038/23468
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