Multivalent Avidity in C-type Lectins: How Glycan Surface Density and Presentation Define Superselective Recognition by DC-SIGN
Year: 2026
Type: preprint
Abstract: Multivalent lectin–glycan interactions (MLGIs) are fundamental to many biological processes. While individual carbohydrate recognition domains (CRDs) determine glycan specificity, their clustering enhances binding affinity and selectivity through multivalency. However, the number of CRDs engaged during binding can vary, and individual CRDs may exhibit weak, non‑specific interactions with off‑target glycans. How these factors collectively shape MLGI behaviour remains unclear. Here, we address this question using a vitally important tetravalent, mannose‑specific C-type lectin DC‑SIGN (4M) and its engineered variants – a heterotetramer containing two mannose‑specific and two galactose‑specific CRDs (2M2G), and a fully galactose‑specific tetramer (4G) – and model surfaces presenting mannose at tuneable densities and defined organisation. We find that DC-SIGN 4M binding increases superlinearly with the increasing mannose density, although such ‘superselective’ recognition is attenuated at high mannose densities (≥50%). Interestingly, DC-SIGN 4M binds more strongly to mannose surfaces diluted by a low-affinity, non-specific galactose over a non-binding hydroxyl-terminated spacer. Whilst both 4M and 4G show weak cross‑binding to surfaces presenting non‑cognate glycans, 4M displays only ~2.7‑fold stronger binding to 100% mannose surface than 2M2G despite its higher mannose-specific valency. Confronting the experimental data with a mathematical model, we quantify the gradually decreasing contributions of the first, second, third and fourth CRD binding to the overall binding avidity, and how these are shaped by the balance of intrinsic CRD-glycan affinity, steric constraints imposed by the glycan surface and conformational constraints imposed by DC-SIGN 4M’s molecular organisation. Together, these results demonstrate that by modulating CRD number and glycan engagement, multivalent lectins can fine‑tune their binding avidity and selectivity for glycan surfaces of varying density and heterogeneity, thus affording them diverse functions and the ability to discriminate heterogeneous glycan environments on cell and pathogen surfaces.
Source: ChemRxiv
Institution: University of Leeds
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221607610