Network and Atomistic Simulations Unveil the Structural Determinants of Mutations Linked to Retinal Diseases

Simona Mariani,Daniele Dell'Orco,Francesca Fanelli,Francesco Raimondi,Angelo Felline,Roland L Dunbrack

doi:10.1371/journal.pcbi.1003207

Abstract

A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would require network-centered approaches combined with atomistic simulations.The transducin G38D mutant associated with the Nougaret Congenital Night Blindness (NCNB) was thoroughly investigated by both mathematical modeling of visual phototransduction and atomistic simulations on the major targets of the mutational effect.Mathematical modeling, in line with electrophysiological recordings, indicates reduction of phosphodiesterase 6 (PDE) recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics (MD) simulations coupled with Functional Mode Analysis improve the resolution of information, showing that such impairment is likely due to disruption of the PDEγ binding cavity in transducin. Protein Structure Network analyses additionally suggest that the observed slight reduction of theRGS9-catalyzed GTPase activity of transducin depends on perturbed communication between RGS9 and GTP binding site. These findings provide insights into the structural fundamentals of abnormal functioning of visual phototransduction caused by a missense mutation in one component of the signaling network. This combination of network-centered modeling with atomistic simulations represents a paradigm for future studies aimed at thoroughly deciphering the structural determinants of genetic retinal diseases. Analogous approaches are suitable to unveil the mechanism of information transfer in any signaling network either in physiological or pathological conditions.

Highlights

A number of incurable diseases in the visual system involve one or more components of the phototransduction signaling network (Figure 1)
Such alterations include the transducin single point mutation G38D associated with the Nougaret Congenital Night Blindness (NCNB)
Sub-microsecond molecular dynamics simulations improve the resolution of information, suggesting that such impairment is likely due to disruption of the effector binding cavity

Summary

Introduction

A number of incurable diseases in the visual system involve one or more components of the phototransduction signaling network (Figure 1). The first event in scotopic vision is the absorption of a photon by rhodopsin (R), the cornerstone of family A of the seven-transmembrane G protein coupled receptors (GPCRs), which leads to the formation of the signaling active state (R*) [3,4] The latter, in turn, catalyzes the exchange of bound GDP for GTP on the abc heterotrimeric G protein transducin (Gt). In this respect, the termination of PDE activation by GaGTP is achieved when the GTP-bound to Ga is hydrolyzed to GDP by the intrinsic GTPase activity of the protein. As a result of the GTPase Activating Protein (GAP) action of RGS, the GaGDP complex reassociates with the bc dimer restoring the GaGDP-bc heterotrimer (i.e. Gt)

Methods

Results

Discussion

Conclusion