Beyond Glycan Binding: Defining Professional Glycoconjugate Counterreceptors in Cellular Systems.

Abstract

Glycan-protein interactions can regulate important biological processes yet are often described in simplistic terms of glycan-binding preferences that imply broad and promiscuous recognition. This conventional ligand-receptor paradigm often fails to distinguish simple binding events from functional binding with downstream biological effects observed in cellular contexts. In this review, we formalize the concept of professional glycoconjugate counterreceptors (PGCRs), which are defined as glycoconjugates whose glycan composition and protein scaffold together enable selective engagement by glycan-binding proteins (GBPs) to drive biological function. We review emerging chemical biology, proteomic, and genetic approaches including proximity labeling, crosslinking mass spectrometry, and CRISPR-based screening, that enable context-dependent identification of PGCRs. These studies reveal that glycan recognition is frequently scaffold-dependent and mediated by discrete glycoproteoforms rather than generic glycan motifs alone. Representative examples, such as Gal-3-CD9 and CD43-Siglec-7 interactions, highlight the importance of integrating binding with functional validation. We envision that a framework shift from a glycan-centric to a glycoconjugate-centric view of molecular recognition can improve our understanding of glycan-dependent signaling particularly in the landscape of druggable biology.

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