Sulfation of tyrosine residues increases activity of the fourth component of complement.

Abstract

Sulfation of tyrosine residues recently has been recognized as a biosynthetic modification of many plasma proteins and other secretory proteins. Effects of this sitespecific modification on protein function are not known, but the activity of several peptides such as cholecystokinin is greatly augmented by sulfation. Here, we examine the role of sulfation in the processing and activity of C4 (the fourth component of complement), one of the few proteins in which sites and stoichiometry of tyrosine sulfation have been characterized.Our results, with C4 as a paradigm, suggest that sulfation of tyrosine residues can have major effects on the activity of proteins participating in protein-protein interactions. Sulfation of C4 synthesized by Hep G2 cells was blocked by incubating the cells with NaCIO3 and guaiacol. These sulfation inhibitors did not alter secretion or other steps in the processing of C4. However, hemolytic activity of C4 was decreased more than 50%. The inhibitors' effect on C4 activity was prevented by adding Na2SO4 to restore sulfation of C4. Activity of C3, a complement component homologous to C4 but lacking tyrosine sulfate residues, was minimally reduced (19%) by the inhibitors. Decreased hemolytic activity of nonsulfated C4 apparently resulted from impaired interaction with complement subcomponent Cli (EC 3.4.21.42), the protease that physiologically activates C4. Purified Cli was able to cleave nonsulfated C4, but 410-fold higher concentrations of Cli were required for that cleavage than to yield equivalent cleavage of sulfated C4. Our results suggest that activation of C4, a central component in the classical pathway of complement activation, is influenced by the level of sulfation of the protein. Thus, sulfation of C4 provides a potential locus for physiological or pharmacological modulation of complement-mediated opsonization and inflammation.

Tyrosine‐rich acidic matrix protein (TRAMP) is a tyrosine‐sulphated and widely distributed protein of the extracellular matrix

“…procollagen III [26], procollagen V [27], fibromodulin [28], fibronectin [29], vitronectin [30], bone sialoprotein [31]) that are known to be posttranslationally modified in this way. Tyrosine sulphation has been shown to be important in the interaction properties of several secreted proteins [29,[32][33][34][35]. Further studies are required to determine if the known interactions of TRAMP, with collagen in fibril assembly [7] and with a putative cell surface receptor in cell adhesion [16], are also influenced by tyrosine sulphation.…”

Analysis of sequence requirements for protein tyrosine sulfation

“…The diverse group of approximately 60 proteins known to be tyrosine sulfated includes regulatory peptides (gastrin and cholecystokinin), plasma proteins associated with clotting (fibrin, alpha2 antiplasmin), proteins of the intercellular matrix (collagen), and membrane-bound enzymes (sucrase-isomaltase and aminopeptidase N). The function of sulfation is largely unknown except for the demonstrated effect of sulfation on the biological activity of peptides and proteins such as cholecystokinin (Huang et al, 1989), hirudin (Stone & Hofsteenge, 1986), complement 4 (Hortin et al, 1989), fibronectin (Suiko & Liu, 1988), and coagulation factor VI11 (Leyte et al, 1991).…”

Thyrotropin regulates tyrosine sulfation of thyroglobulin

“…Bound to ¹TSH ¹TSHþKI þTSH þTSHþKI ¹TSH/þTSH ¹TSHþKI/þTSHþKI in activation-deactivation of biological activities of different proteins (6)(7)(8)(9); the sulfated residues bound to tyrosines could be involved in hormonogenesis and the control of tyrosine sulfation of thyroglobulin by TSH could be related to this process. The presence of an acidic or neutral amino acid adjoining the amine side of tyrosine residue has been reported to be a necessary condition for tyrosine sulfation (44)(45)(46).…”

“…Sulfate residues are present on carbohydrate units (for review see (5)) and on some amino acids, especially tyrosine (2)(3)(4). The roles and functions of these sulfate residues differ: they are probably involved in the molecular conformations of proteins and in proteinprotein interactions, and they can have a role in the process of activation-deactivation of protein biological activities, particularly when they are bound to tyrosine molecules (6)(7)(8)(9). However, the functions of sulfate residues on numerous proteins are not understood, and little has been reported on the regulation of sulfate binding.…”