Multivalent Avidity in C-type Lectins: How Glycan Surface Density and Presentation Define Superselective Recognition by DC-SIGN
7 affiliations
- 1Faculty of Health and Life Sciences
- 2University of Leeds
- 3Astbury Centre for Structural Molecular Biology
- 4Faculty of Environment
- 5School of Chemistry, Faculty of Engineering and Physical Sciences
- 6Faculty of Engineering and Physical Sciences
- 7Bragg Centre for Materials Research
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.
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BibTeX
@misc{tait2026multivalent,
title = {{Multivalent Avidity in C-type Lectins: How Glycan Surface Density and Presentation Define Superselective Recognition by DC-SIGN}},
author = {Erin Tait and Qian Peng and Darshita Budhadev and Rammile Ettelaie and Dejian Zhou and Ralf P. Richter and Yuan Guo},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010352/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010352/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Multivalent Avidity in C-type Lectins: How Glycan Surface Density and Presentation Define Superselective Recognition by DC-SIGN
AU - Erin Tait
AU - Qian Peng
AU - Darshita Budhadev
AU - Rammile Ettelaie
AU - Dejian Zhou
AU - Ralf P. Richter
AU - Yuan Guo
PY - 2026
DA - 2026/10/13
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010352/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010352/v1
AB - 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.
ER -