GALNT11 Controlled O-glycans Modulate Ligand Interactions of the Endocytic Receptor LRP1

Low-density lipoprotein receptor (LDLR) and LDLR-related proteins (LRPs) are essential endocytic receptors and regulators of multiple physiological processes including protein reabsorption, cholesterol clearance, and neuronal protein trafficking. Previously, we identified O-GalNAc glycans within ligand-binding regions of LRP receptors, with functional implications for the uptake of LDL (via LDLR) and albumin (via LRP2). Notably, these O-glycans are specifically introduced by GALNT11, one of 20 GALNT isoenzymes. Here, we used cell models to investigate the role of GALNT11-mediated glycosylation in modulating ligand interactions of the widely expressed receptor LRP1. We find that while GALNT11-specific glycosylation does not alter LRP1-mediated uptake of ligands such as ApoE and RAP, it significantly affects the uptake of tau, amyloid beta and Hemopexin. We further show that GALNT11 O-glycans on LRP1 are selectively hyposialylated, and molecular dynamics simulations reveal that their sialylation can prevent glycan-ligand interactions.