Structural Dynamics in Rhodopsin Activation and Attenuation

Oregon Health & Science University, Portland OR

Investigators

Linked publications & trials

Abstract

Project Summary Understanding of how vision occurs in humans, and how some retinal diseases affect this process, requires a mechanistic and molecular level understanding of the proteins involved. Over the past two decades, significant progress has been made in unraveling the intricate molecular processes involved in human vision, especially in low-light conditions. Detailed insights have been gained into the activation of rhodopsin, the photoreceptor responsible for dim-light vision, including the pathways, factors affecting its chemical reactions, and the stability of its retinal attachment. There has even been considerable success in obtaining structural information about rhodopsin in various states, as well as the structures of proteins it interacts with, such as the G protein transducin, rhodopsin kinase, and arrestin. Complex structures of activated rhodopsin in partnership with these signaling molecules are also now available. However, our understanding of color vision, mediated by cone opsins, is quite limited in comparison. There is essentially no structural data for any cone opsin, and their interactions with signaling partners remains a relatively uncharted territory. Moreover, we lack other basic, fundamental knowledge about cone opsins, such as the kinetics of their activation and the reasons behind the instability and rapid release of their retinal ligand. The goal of our competitive renewal is to address these gaps in our knowledge, focusing primarily on the human green cone opsin (hGCO). Our objectives include unraveling the kinetics of hGCO photoactivation, investigating the mechanisms behind its swift decay after activation, and utilizing this information to determine the structure of hGCO. We feel our proposed work is important and long overdue. A detailed understanding of how cone opsins function, including their activation, retinal binding, and interactions with signaling partners is essential for the development of pharmaceuticals targeting these crucial receptors. Furthermore, our discoveries and methodologies are expected to have broad implications for the wider field of vision research, with the potential to enhance human health outcomes.