Posttranslational modifications of proteins in diseased retina

Abstract

Posttranslational modifications (PTMs) are known to constitute a key step in protein biosynthesis and in the regulation of protein functions. Recent breakthroughs in protein purification strategies and current proteome technologies make it possible to identify the proteomics of healthy and diseased retinas. Despite these advantages, the research field identifying sets of posttranslationally modified proteins (PTMomes) related to diseased retinas is significantly lagging, despite knowledge of the major retina PTMome being critical to drug development. In this review, we highlight current updates regarding the PTMomes in three retinal degenerative diseases-namely, diabetic retinopathy (DR), glaucoma, and retinitis pigmentosa (RP). A literature search reveals the necessity to expedite investigations into essential PTMomes in the diseased retina and validate their physiological roles. This knowledge would accelerate the development of treatments for retinal degenerative disorders and the prevention of blindness in affected populations.

Keywords: PTMomes; diabetic retinopathty; glaucoma; inherited retinal degeneration (IRD); post translation modification.

FIGURE 1

Rhodopsin as a model for understanding the importance of posttranslational modifications. (A) Simplified depiction of rhodopsin phosphorylation. Transducin’s interaction with RHO is impeded by RHO’s phosphorylation by rhodopsin kinase at multiple C-terminal amino acids. Arrestin preferentially binds to RHO that has been phosphorylated. The R135L RHO mutation results in RHO hyperphosphorylation. S334Ter RHO lacks many C-terminal residues and therefore lacks critical phosphorylation sites. (B) RHO is palmitoylated at two C terminal cysteines that promotes its homodimerization. (C) N-terminal N-glycosylation of RHO plays a role in its protein folding, stability and membrane trafficking. The T17M mutation interferes with the enzymatic glycosylation of the N-terminal asparagine residues, impeding RHO folding and outer segment trafficking.