Abstract
Tyrosine sulfation, a post-translational modification, can determine and often enhance protein-protein interaction specificity. Sulfotyrosyl residues (sTyrs) are formed by the enzyme tyrosyl-protein sulfotransferase during protein maturation in the Golgi apparatus and most often occur singly or as a cluster within a six-residue span. With both negative charge and aromatic character, sTyr facilitates numerous atomic contacts as visualized in binding interface structural models, thus there is no discernible binding site consensus. Found exclusively in secreted proteins, in this review, we discuss the four broad sequence contexts in which sTyr has been observed: first, a solitary sTyr has been shown to be critical for diverse high-affinity interactions, such as between peptide hormones and their receptors, in both plants and animals. Second, sTyr clusters within structurally flexible anionic segments are essential for a variety of cellular processes, including coreceptor binding to the HIV-1 envelope spike protein during virus entry, chemokine interactions with receptors, and leukocyte rolling cell adhesion. Third, a subcategory of sTyr clusters is found in conserved acidic sequences termed hirudin-like motifs that enable proteins to interact with thrombin; consequently, many proven and potential therapeutic proteins derived from blood-consuming invertebrates depend on sTyrs for their activity. Finally, several proteins that interact with collagen or similar proteins contain one or more sTyrs within an acidic residue array. Refined methods to direct sTyr incorporation in peptides synthesized both in vitro and in vivo, together with continued advances in mass spectrometry and affinity detection, promise to accelerate discoveries of sTyr occurrence and function.