Abstract
Lack of tyrosine sulfation of ocular proteins results in disorganized photoreceptor structure and drastically reduced visual function, demonstrating the importance of this post-translational modification to vision. To understand the role that tyrosine sulfation plays in the function of ocular proteins, we identified some tyrosine-sulfated proteins in the retinal pigment epithelium using two independent methods, immuno-affinity column purification with an anti-sulfotyrosine specific antibody and computer-based sequence analysis of retinal pigment epithelium secretome by means of the prediction program Sulfinator. Radioactive labeling followed by thin layer electrophoresis revealed that three proteins, vitronectin, opticin, and complement factor H (CFH), were post-translationally modified by tyrosine sulfation. The identification of vitronectin and CFH as tyrosine-sulfated proteins is significant, since both are deposited in drusen in the eyes of patients with age-related macular degeneration (AMD). Furthermore, mutations in CFH have been determined to be a major risk factor in the development of AMD. Future studies that seek to understand the role of CFH in the development of AMD should take into account the role that tyrosine sulfation plays in the interaction of this protein with its partners, and examine whether modulating sulfation provides a potential therapeutic target.
Highlights
Tyrosine O sulfation, a post-translational modification employed in higher eukaryotes [1], is catalyzed by two Type II transmembrane enzymes, tyrosylprotein sulfotransferases 1 & 2 (TPST 1 & 2)
The analysis revealed that the retinal pigment epithelium (RPE) harbors a relatively higher number of tyrosine-sulfated proteins than the neurosensory retina in each of the four mammalian species tested (Figure 1)
The tyrosine-sulfated proteins in human lysates appear more prominent when compared to those in other species. This may be partly due to the fact that PSG2 was raised against the tyrosinesulfated N terminus of human PSGL-1 [19], and may better recognize human tyrosine-sulfated proteins
Summary
Tyrosine O sulfation, a post-translational modification employed in higher eukaryotes [1], is catalyzed by two Type II transmembrane enzymes, tyrosylprotein sulfotransferases 1 & 2 (TPST 1 & 2) It was initially described by Bettelheim in 1954, but was later found to be a common post-translational modification [2,3]. Tyrosine sulfation occurs in the trans-Golgi compartment and requires 39-phosphoadenosine 59-phosphosulfate (PAPS) as a sulfate donor for the reaction [4]. It is only observed on secreted and transmembrane proteins: nuclear and cytoplasmic proteins have not been reported to have this modification [1,5]. Later studies showed that some tyrosine-sulfated proteins do not follow these criteria, and it is the secondary structure that may expose the tyrosine residue to a TPST to be sulfated [10]
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