The ligand preference of LRP1 is regulated by O-glycans.

The family of low-density lipoprotein receptor (LDLR) and LDLR-related proteins (LRPs) are endocytic receptors serving as essential regulators of multiple physiological processes including cholesterol clearance, protein reabsorption, and neuronal protein trafficking. Site-specific O-glycans modify linkers of the ligand-binding domains of LRPs. Most linker O-glycans are initiated exclusively by GALNT11, 1 of 20 polypeptide GalNAc-transferase isoenzymes. Here, we investigate the role of GALNT11 linker O-glycans in the large and widely expressed multiligand receptor LRP1. In cell models expressing LRP1 with and without GALNT11, we demonstrate that while the uptake of certain ligands such as RAP and ApoE was unaffected, uptake of neurotoxic tau and amyloid-β was altered and in opposite directions. Characterization of LRP1 linker O-glycans indicated incomplete sialic acid capping, a feature that, in MD simulations, enabled inter- and intramolecular interactions. Our findings highlight a potential regulatory mechanism of endocytic receptors and identify the ligand repertoire of LRP1 as influenced by O-glycans, with implications for neurodegenerative disease.