Chlorophyll-Derivative Modulation of Rhodopsin Signaling Properties through Evolutionarily Conserved Interaction Pathways.

Kristina N Woods,Judith Klein-Seetharaman,Jürgen Pfeffer

doi:10.3389/fmolb.2017.00085

Abstract

Retinal is the light-absorbing chromophore that is responsible for the activation of visual pigments and light-driven ion pumps. Evolutionary changes in the intermolecular interactions of the retinal with specific amino acids allow for adaptation of the spectral characteristics, referred to as spectral tuning. However, it has been proposed that a specific species of dragon fish has bypassed the adaptive evolutionary process of spectral tuning and replaced it with a single evolutionary event: photosensitization of rhodopsin by chlorophyll derivatives. Here, by using a combination of experimental measurements and computational modeling to probe retinal-receptor interactions in rhodopsin, we show how the binding of the chlorophyll derivative, chlorin-e6 (Ce6) in the intracellular domain (ICD) of the receptor allosterically excites G-protein coupled receptor class A (GPCR-A) conserved long-range correlated fluctuations that connect distant parts of the receptor. These long-range correlated motions are associated with regulating the dynamics and intermolecular interactions of specific amino acids in the retinal ligand-binding pocket that have been associated with shifts in the absorbance peak maximum (λmax) and hence, spectral sensitivity of the visual system. Moreover, the binding of Ce6 affects the overall global properties of the receptor. Specifically, we find that Ce6-induced dynamics alter the thermal stability of rhodopsin by adjusting hydrogen-bonding interactions near the receptor active-site that consequently also influences the intrinsic conformational equilibrium of the receptor. Due to the conservation of the ICD residues amongst different receptors in this class and the fact that all GPCR-A receptors share a common mechanism of activation, it is possible that the allosteric associations excited in rhodopsin with Ce6 binding are a common feature in all class A GPCRs.

Highlights

The dimmest habitats on earth appear at night and in the depths of the ocean (Warrant, 2004)
The differences in the spectra of the two receptors suggest that binding of Ce6 alters the conformational ensemble dynamics in rhodopsin
We identify long-range conserved interactions in rhodopsin that are excited by the binding of an allosteric modulator (Ce6) in the cytoplasmic domain of the receptor

Summary

Introduction

The dimmest habitats on earth appear at night and in the depths of the ocean (Warrant, 2004). The greatest challenge for vision in these habitats is capture of photons, and the way these photons are post-processed. The primary photoreceptor in eyes, rhodopsin, is a major target for adaptation to different light conditions. Rhodopsin as the prototypical member of the GPCR-A family adopts an Chlorophyll-Derivative Modulation of Rhodopsin Signaling photosensitizing effects of chlorophyll-derivatives observed in salamander and deep-sea fish can be reproduced qualitatively using bovine rhodopsin, in vitro (Washington et al, 2004). Ce6 suggested that the sensitivity of rhodopsin can be broadened to blue and red light in the presence of Ce6 (Washington et al., 2007). The photosensitizing effect of Ce6 and other porphyrin compounds in vision has been reported as a side-effect during photodynamic therapy (Kimura, 1987)

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