Emerging patterns of tyrosine sulfation and O-glycosylation cross-talk and co-localization

[Display omitted] •A growing body of evidence shows O-glycosylation and tyrosine sulfation co-localize in important functional protein domains in a broad range of protein classes.•Recent advances in methods and technologies now allow for more detailed dissection of these patterns.•The co-localization of O-glycosylation and tyrosine sulfation occur in functionally important domains making it highly relevant for future drug discovery. Post-translational modifications (PTMs) drive the diversity of the proteome and broadly regulate protein function. Interplay between different types of PTMs further enables tight and dynamic fine-tuning of molecular functions. O-Glycosylation on serine, threonine, and tyrosine residues is a major PTM with diverse roles in development, differentiation, pathogenesis, and proteolytic processing. Other examples of cross-talk between PTMs also exist, such as PSGL-1, where the combined presence of N-terminal sulfotyrosines and O-glycans is pivotal for selectin binding. A handful of other related examples of O-glycans and sulfotyrosine co-localization has been described but it is not yet recognized as a general regulatory phenomenon. In this review, we highlight the emerging global pattern of co-localization of cell-surface and extracellular sulfotyrosines with O-glycans, which we term ‘multi-motif’ interactions, from a wide range of protein classes. We also discuss the barriers, and existing and future tools needed to dissect the biological impact and biomedical potential.