Tyrosine O-sulfation is a post-translational modification mediated by one of two Golgi tyrosylprotein sulfotransferases (TPST-1 and -2) expressed in all mammalian cells. Tyrosine sulfation plays an important role in the function of some known TPST substrates by enhancing protein-protein interactions. To explore the role of these enzymes in vivo and gain insight into other potential TPST substrates, TPST-2-deficient mice were generated by targeted disruption of the Tpst2 gene. with wild type sperm, but sperm-egg fusion is similar or even increased. These data strongly suggest that tyrosine sulfation of unidentified substrate(s) play a crucial role in these processes and document for the first time the critical importance of post-translational tyrosine sulfation in male fertility.Tyrosine O-sulfation is a widespread post-translational modification that was first described about 50 years ago (1, 2). Tyrosine-sulfated proteins and/or tyrosylprotein sulfotransferase (TPST) 5 activity have been described in many species throughout the plant and animal kingdoms, including Volvox carteri, one of the earliest multicellular organisms. At this time, 37 tyrosine-sulfated proteins have been identified in humans, many of which play important roles in inflammation, hemostasis, immunity, and other processes (3-5). These include certain adhesion molecules, G-protein-coupled receptors, coagulation factors, serpins, extracellular matrix proteins, hormones, and others. It has been demonstrated that some of these proteins require tyrosine sulfation for optimal function (3). Nevertheless, it is very likely that we are only beginning to appreciate the complexity of the TPST substrate repertoire.In mice and humans, tyrosine O-sulfation is mediated by one of two tyrosylprotein sulfotransferases, called TPST-1 and TPST-2, which are localized to the trans-Golgi network (7-9). Mouse TPST-1 and -2 are 370-and 376-residue type II transmembrane proteins, respectively. Each has a short N-terminal cytoplasmic domain, followed by a single ϳ17-residue transmembrane domain, a membrane-proximal ϳ40-residue stem region, and a luminal catalytic domain containing four conserved cysteine residues and two N-glycosylation sites. The amino acid sequence of human and mouse TPST-1 are ϳ96% identical, and human and mouse TPST-2 have a similar degree of identity. TPST-1 is ϳ65-67% identical to TPST-2 in both humans and mice. Both isoenzymes are broadly expressed in human and murine tissues and cell lines and are co-expressed in most, if not all, cell types (3). However, the relative abundance of the two proteins in tissues and cells is uncertain. The human TPST1 and TPST2 genes are on 7q11.21 and 22q12.1, respectively. The mouse Tpst1 and Tpst2 genes are ϳ18.5 megabase pairs apart on chromosome 5.In vitro studies using synthetic peptide acceptors indicate that the two TPST isoenzymes differ in substrate preference. Peptides modeled on the N terminus of P-selectin glycoprotein ligand-1 are sulfated by the two isoenzymes with equal efficiency. In contrast, pept...
Protein-tyrosine sulfation is a post-translational modification of an unknown number of secreted and membrane proteins mediated by two known Golgi tyrosylprotein sulfotransferases (TPST-1 and TPST-2). Tpst double knockouts were generated to investigate the importance of tyrosine sulfation in vivo. Double knockouts were born alive at the expected frequency, were normal in size, and their tissues do not synthesize sulfotyrosine. However, most pups die in the early postnatal period with signs of cardiopulmonary insufficiency. A combination of clinical, magnetic resonance imaging, and histological data indicated that lungs of Tpst double knockouts fail to expand at birth resulting in acute pulmonary hypertension, right-to-left shunting, and death by asphyxia in the early postnatal period. Some double knockouts survive the postnatal period, but fail to thrive and display delayed growth that is due in part to hypothyroidism. In addition, we find that Tpst2−/− mice have primary hypothyroidism, but that Tpst1−/− mice are euthyroid. This suggests that a protein(s) required for thyroid hormone production is sulfated and cannot be sulfated in the absence of TPST-2. Thus, Tpst1 and Tpst2 are the only Tpst genes in mice, tyrosine sulfation is required for normal pulmonary function at birth, and TPST-2 is required for normal thyroid gland function.
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