Sulfotyrosine residues: Interaction specificity determinants for extracellular protein–protein interactions

A potential antibody repertoire diversification mechanism through tyrosine sulfation for biotherapeutics engineering and production

“…Subsequently, several other types of unconventional mechanisms which utilize various PTMs to regulate humoral immune responses and antibody diversification have been discovered [reviewed by ( 31 )]. Over the past twenty years, a significant understanding upon the molecular mechanisms of Tyr-sulfation modification and the biological function of the resulting sulfo-Tyr (sTyr) has been shown in protein-protein interaction for peptide hormones, cell surface receptors, virus entry, chemokine signaling, and blood clotting enzymes [see recent reviews, ( 23 – 26 , 32 , 33 )]. New examples and mechanistic insights for the role of sTyr in modulating antibody diversification have been reported ( 28 , 34 – 47 ).…”

“… (A) Mechanisms of Tyr-sulfation in mammalian cells. (B) Primary structures of human TPST and plant TPST ( 25 , 26 ) (created with ). Conserved residue Lys (R) in 5’-PSB, Ser (S) in 3’-PB, and catalytic base residue His (H) and Glu (E) are depicted.…”

“…The tyrosylprotein sulfotransferases (TPSTs) pathway ( 48 , 49 ) is the key synthesis pathway for Tyr-sulfation in antibody. Biological utilization of inorganic sulfate for sTyr, and other sulfated biomolecules (sulfated carbohydrates, or neurotransmitters), requires the metabolic activation into adenosine-5’-phosphosulfate (APS) by ATP sulfurylase (ATPS) and further into 3’-phosphoadenosine-5’-phosphosulfate (PAPS) by APS kinase ( 22 , 23 , 25 , 26 , 32 , 33 , 50 ). In animal cells, the APS and ATPS are fused to form a single bifunctional PAPS synthase (PAPSS).…”

“…Tyr sulfation was first reported nearly seventy years ago ( 61 ), yet its physiological significance and link to diseases haven’t begun to be appreciated until the cloning of TPST genes more than two decades ago ( 48 , 49 ). TPSTs are widely expressed in most tissues, and conserved from worm to mammals, and plants but not in yeast and most of the prokaryotes ( 22 , 23 , 25 , 26 ). Human TPST1 and 2 exhibit different expression patterns, e.g., TPST1 is more in testis and TPST2 is more in the blood, trachea, thyroid gland, and several other organs ( 25 ).…”

“…These two isoform enzymes also have different substrate specificities ( 62 – 64 ) and distinct mouse knockout phenotypes ( 65 , 66 ), indicating a difference in specific biological functions ( 65 – 67 ). Animal TPSTs are type II membrane glycoproteins with a length of around 370 amino acids ( 25 , 26 ). Like those of the cytoplasmic sulfotransferases and saccharide sulfotransferases, the enzymatic domain of TPSTs contains two short sequence motifs, termed 5’-phosphosulfate binding motif (PSB) and 3’-phosphate binding (PB) motif, and a catalytic base residue (His or Glu).…”