Sensory receptor retinal-binding proteins are major mediators in light signal transduction. The best characterized transmembrane sensory receptors are rhodopsin, a paradigm of the G protein-coupled receptor superfamily, and sensory rhodopsin II from halophilic archeabacteria. Rhodopsin uses light to trigger the initial steps in a cascade that culminates in vision, while sensory rhodopsin II uses light to initiate a phosphorylation cascade that regulates the cell's flagellar motors in order to control phototaxis. We very recently elucidated the crystal structure of SRII to 2.1 A resolution, allowing us now to elucidate the mechanisms of light signal transduction. Moreover, in a parallel computational work, we identified the physical determinants that regulate color tuning. However, this structure of SRII in the ground state represents only a single step along a complex reaction pathway, which starts with photoexcitation, followed by conformational changes of the receptor, and transmission of the light signal to cognate proteins. Clearly, to fully understand the mechanism of sensory signaling mediated by SRII we require insight into the atomic structures of the intermediates along this signaling pathway, as well as the structure of the SRII-HtrII complex. This project addresses a fundamental question: How does retinal photoisomerization trigger protein structural changes that lead to activation of the transducer, thereby initiating the sensory response?Answering this question is essential for elucidating the molecular mechanisms of signal transduction mediated by sensory receptors.
The aims of this project are to identify the structural movements in SRII that culminate in the formation of the signaling state of the receptor, by trapping and solving the structures of the 1) K- and 2) M-intermediates, 3) elucidate the mechanism by which SRII recognizes and binds its cognate transducer protein, by solving the X-ray structure of the ground-state SRII-HtrII complex, and 4) identify the structural determinants of sensory rhodopsin I, which can act as a photoattractant and photorepellent, by solving its X-ray structure. Achieving these Specific Aims should allow us finally to elucidate, at high resolution the molecular mechanisms of sensory rhodopsin-mediated signaling. These are expected to be similar to that of visual rhodopsin, and so relevant to a molecular understanding of the mechanism of vision in health and disease.
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