Dynamic N-glycan rearrangement nucleates galectin-3 oligomers and drives endocytosis

Membrane glycoproteins often adopt different conformations when shifting between active and inactive states. Here, we discover a molecular switch that operates through major changes in the spatial arrangement of the N-glycan landscape during such conformational transitions. We demonstrate that the cell adhesion glycoprotein alpha5 beta1 integrin selectively in its bent-closed inactive conformational state nucleates the formation of ring-shaped tetramers of the glycan-binding protein galectin-3 to drive endocytic uptake. We propose a novel structural model to explain how spatial rearrangement of N-glycans transduced by conformational changes results in galectin-3 tetramers. Our findings identify local arrangements of N-glycans as unexpectedly dynamic regulatory elements at the cell surface and provide a new facet to higher order pattern interactions with glycoproteins for regulation of processes such as galectin-dependent endocytosis.