The Ligand Preference of LRP1 is Regulated by O-glycans

Low-density lipoprotein receptor (LDLR) and LDLR-related proteins (LRPs) are endocytic receptors serving as essential physiological regulators of multiple processes including cholesterol clearance, protein reabsorption and neuronal protein trafficking. We originally discovered O-glycans in linkers of the ligand-binding domains of LDLR/LRP receptors and showed that these play critical roles for uptake of LDL by LDLR and albumin by LRP2. Remarkably, these linker O-glycans are introduced exclusively by GALNT11, one out of 20 polypeptide GalNAc-transferase isoenzymes. Here, we investigate the role of linker O-glycans on the large (~600 kDa) and widely expressed multiligand LRP1 receptor implicated in diseases including neuropathies. In genetically engineered cell models we activated endogenous full-coding LRP1 with and without O-glycans and demonstrate that while the uptake of certain ligands, such as RAP and ApoE, was unaffected by O-glycans, the uptake of the neurotoxic molecules tau and amyloid beta was altered and in opposite directions. This demonstrates that O-glycans in ligand-binding domains can differentially modulate ligand affinity and specificity of LRP1. Our findings highlight an overlooked regulatory mechanism of endocytic receptors and identify the ligand repertoire of LRP1 as being influenced by O-glycans, with potential implications for neurodegenerative disease.