Role of tyrosine-sulfated proteins in retinal structure and function

Abstract

The extracellular matrix (ECM) plays a significant role in cellular and retinal health. The study of retinal tyrosine-sulfated proteins is an important first step toward understanding the role of ECM in retinal health and diseases. These secreted proteins are members of the retinal ECM. Tyrosine sulfation was shown to be necessary for the development of proper retinal structure and function. The importance of tyrosine sulfation is further demonstrated by the evolutionary presence of tyrosylprotein sulfotransferases, enzymes that catalyze proteins' tyrosine sulfation, and the compensatory abilities of these enzymes. Research has identified four tyrosine-sulfated retinal proteins: fibulin 2, vitronectin, complement factor H (CFH), and opticin. Vitronectin and CFH regulate the activation of the complement system and are involved in the etiology of some cases of age-related macular degeneration. Analysis of the role of tyrosine sulfation in fibulin function showed that sulfation influences the protein's ability to regulate growth and migration. Although opticin was recently shown to exhibit anti-angiogenic properties, it is not yet determined what role sulfation plays in that function. Future studies focusing on identifying all of the tyrosine-sulfated retinal proteins would be instrumental in determining the impact of sulfation on retinal protein function in retinal homeostasis and diseases.

Keywords: extracellular matrix; retina; retinal diseases; tyrosine sulfation.

Figure 1. Known biologically significant tyrosine-specific post-translational modification to proteins

Tyrosine undergoes enzymatic sulfation and phosphorylation and non-enzymatic nitration that is mediated by reactive nitrogen species.

Figure 2. Pathway of tyrosine sulfation

Free sulfate enter the cell via sulfate transporters and are rapidly converted to 3’-phosphoadenosine 5’-phosphosulfate (PAPS) by 3’-phosphoadenosine 5’-phosphosulfate synthase. 3’-phosphoadenosine 5’-phosphosulfate is then translocated into the trans-Golgi through 3’-phosphoadenosine 5’-phosphosulfate translocase. This allows the tyrosylprotein sulfotransferase to then add the free sulfate from the high energy source, 3’-phosphoadenosine 5’-phosphosulfate, to a newly synthesized protein. The tyrosine sulfated protein is secreted to become a free member of the extracellular matrix or re-associate with the producing cell directly or through interactions with membrane proteins.