Design–functionality relationships for adhesion/growth-regulatory galectins
Open Access
- 4 February 2019
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 116 (8), 2837-2842
- https://doi.org/10.1073/pnas.1813515116
Abstract
Glycan-lectin recognition is assumed to elicit its broad range of (patho)physiological functions via a combination of specific contact formation with generation of complexes of distinct signal-triggering topology on biomembranes. Faced with the challenge to understand why evolution has led to three particular modes of modular architecture for adhesion/growth-regulatory galectins in vertebrates, here we introduce protein engineering to enable design switches. The impact of changes is measured in assays on cell growth and on bridging fully synthetic nanovesicles (glycodendrimersomes) with a chemically programmable surface. Using the example of homodimeric galectin-1 and monomeric galectin-3, the mutual design conversion caused qualitative differences, i.e., from bridging effector to antagonist/from antagonist to growth inhibitor and vice versa. In addition to attaining proof-of-principle evidence for the hypothesis that chimera-type galectin-3 design makes functional antagonism possible, we underscore the value of versatile surface programming with a derivative of the pan-galectin ligand lactose. Aggregation assays with N,N′-diacetyllactosamine establishing a parasite-like surface signature revealed marked selectivity among the family of galectins and bridging potency of homodimers. These findings provide fundamental insights into design-functionality relationships of galectins. Moreover, our strategy generates the tools to identify biofunctional lattice formation on biomembranes and galectin-reagents with therapeutic potential.Keywords
Funding Information
- NSF | MPS | Division of Materials Research (DMR-1066116)
- NSF | MPS | Division of Materials Research (DMR-1807127)
- NSF | MPS | Division of Materials Research (DMR-1120901)
- NSF | MPS | Division of Materials Research (DMR-1120901)
- Spanish BFU (2016-77835R)
- Science Foundation Ireland (13/IA/1959)
- HHS | NIH | National Institute of General Medical Sciences NCI (NCI R21-CA178754)
- China Scholarship Council (China)
- P. Roy Vagelos Chair (University of Pennsylvania)
- Alexander von Humboldt Foundation (Germany)
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