Sulfation of the Human Cytomegalovirus Protein UL22A Enhances Binding to the Chemokine RANTES

UL22A is an 83 amino acid chemokine‐binding protein produced by human cytomegalovirus that likely assists the virus in dampening the host antiviral response. We proposed that UL22A is sulfated on two tyrosine residues and tested this hypothesis through the chemical synthesis of a small library of differentially sulfated protein variants. The (sulfo)proteins were efficiently prepared using a novel β‐selenoleucine motif to facilitate one‐pot ligation–deselenization chemistry. Tyrosine sulfation of UL22A proved critical for RANTES binding, with the doubly sulfated variant exhibiting an improvement in binding of 2.5 orders of magnitude compared to the unmodified protein. Modifications matter: The chemokine‐binding protein UL22A was predicted to be post‐translationally sulfated on two tyrosine residues. A library of sulfated UL22A proteins was constructed through a one‐pot synthesis using a novel β‐selenoleucine‐mediated peptide ligation reaction followed by deselenization chemistry. Binding experiments showed that sulfation of the tyrosine residues substantially enhances the binding affinity for the chemokine RANTES.