Deglycosylation induces a novel distal conformation in the mannose receptor CD206.

Deglycosylation can disrupt protein structure and dynamics in ways that compromise function. In this study, we examine the structural and functional consequences of N-glycan removal in the mannose receptor CD206, a multi-domain lectin involved in innate immunity. Using atomistic molecular dynamics simulations and AlphaFold-predicted full-length models, we provide the first comprehensive structural and dynamical characterization of CD206, which remains unresolved by experimental methods. Our simulations reveal that deglycosylation enables access to a previously undescribed concave conformational state in the distal lectin domains CTLD7-8, in contrast to the glycosylated form, which remains restricted to a convex arrangement. Principal component and normal mode analyses show that this conformational switch is tightly linked to the presence of glycosylation in certain residues, which constrains receptor flexibility and reduces conformational sampling. While both conformations share an extended global architecture, they differ in curvature, potentially influencing ligand accessibility. Functional assays with α-D-mannopyranoside (MMA), a natural-occurring ligand of CD206, and the CD206-binding tumor-homing peptide mUNO show that deglycosylation weakens canonical ligand retention and exposes new interaction sites, including regions normally shielded by glycans. These findings suggest that altered glycosylation, as seen in pathological conditions like cancer, can reshape the receptor's conformational and binding landscape, ultimately influencing immune recognition and offering new opportunities for therapeutic targeting.