Rhodopsin Oligomerization and Aggregation

Abstract

Rhodopsin is the light receptor in photoreceptor cells of the retina and a prototypical G protein-coupled receptor. Two types of quaternary structures can be adopted by rhodopsin. If rhodopsin folds and attains a proper tertiary structure, it can then form oligomers and nanodomains within the photoreceptor cell membrane. In contrast, if rhodopsin misfolds, it cannot progress through the biosynthetic pathway and instead will form aggregates that can cause retinal degenerative disease. In this review, emerging views are highlighted on the supramolecular organization of rhodopsin within the membrane of photoreceptor cells and the aggregation of rhodopsin that can lead to retinal degeneration.

Keywords: G protein-coupled receptor; Photoreceptor cell; Phototransduction; Quaternary structure; Retina; Retinal degeneration.

Figure 1.

Cartoon of a rod photoreceptor cell. Rod photoreceptor cells contain a rod outer segment and rod inner segment. The rod outer segment contains stacks of membranous discs, which are shown in a side view and top view. Rhodopsin (red) is densely packed within the membrane of the discs, forming nanodomains of oligomeric receptor. This figure is reprinted from (Rakshit et al. 2017), with permission from Elsevier.

Figure 2.

Equilibrium of different oligomeric forms of rhodopsin. A. A general schematic showing a chemical equilibrium among differently sized oligomers (denoted by the superscript) of a receptor (R). The equilibrium dissociation constants determined for rhodopsin are denoted (Mishra et al. 2016). B-E. A summary of analysis of AFM images of ROS disc membranes is shown. Data from mice housed under cyclic light, 10 days constant dark, or 10 days constant light conditions is shown in panels B and C and data from mice housed under 10, 20, or 30 days constant dark conditions is shown in panels D and E. Histograms of nanodomain sizes (B and D) and rhodopsin density within the membrane (C and E) are shown. The nanodomain size reflects the size of the rhodopsin oligomer. The histograms are reproduced from (Rakshit et al. 2017), with permission from Elsevier. F. The predominant oligomeric species of rhodopsin in photoreceptor membranes is a 24-mer. The changes in the complement of rhodopsin nanodomains/oligomers illustrated in panels B and D can be described in terms of a shift in equilibrium between a 24-mer and larger sized oligomers.

Figure 3.

Mutations in rhodopsin that cause misfolding and aggregation. Partial (blue) and complete (yellow) misfolding mutations in rhodopsin are illustrated on the secondary structure (A) and tertiary structure (B) of rhodopsin. Mutation of proline at position 267 (green) can be either partial or complete, depending on the specific mutation. The chromophore 11-cis retinal is shown as pink spheres. The figure is reprinted from (Gragg and Park 2019), with permission from Elsevier.