Galectin-1 Interactions with complex glycans and Alpha-linked carbohydrates

Abstract

Galectin-1 (gal-1) is defined as an alpha-galactoside-binding protein, which crosslinks apposing glycans to mediate cell-cell and cell-extracellular matrix interactions. In this way, gal-1 facilitates cellular adhesion and migration and induces signaling pathways for growth and regulation. Gal-1 is overexpressed in an array of human cancers and correlates with poor patient prognosis. Reports on the role of gal-1 in malignant growth provide evidence that gal-1 is involved in tumor immune escape and is essential for angiogenesis as well as promoting metastasis. For these reasons, gal-1 is considered a good target for novel cancer therapeutics. Towards this goal, we used NMR spectroscopy to probe the binding of gal-1 to complex carbohydrates such as davanat, a galactomannan poised to enter into phase III clinical trials for the treatment of metastatic colorectal cancer, and GRG, a galactorhamnogalacturonate being developed as an oncological therapeutic. We found that davanat, an alpha-galactoside, interacts with a novel region on gal-1, outside of its conventional carbohydrate binding site, while GRG interacts at an area that includes and extends out from the carbohydrate binding site. Additionally, we found that gal-1 affects the hydrodynamic behavior of these glycans, and based on these findings, we hypothesized that gal-1 has a role in decongesting cell-surface glycans, which may assist in the formation of plasma-membrane microdomains. These results spurred additional studies with alpha-linked disaccharides and a series of galactomannans with varying Man/Gal ratios. Overall, this work contributes to an expanded understanding of gal-1/glycan interactions, which will be useful towards the design and optimization of gal-1 targeting drugs.