BPS2026 – Elucidating receptor ligand interactions between tau and LRP1

The low-density lipoprotein receptor (LDLR) family is a group of proteins crucial to cholesterol homeostasis. As a member of the family, LRP1 is a cell surface receptor composed of an extracellular α-chain and an intracellular β-chain. Complement repeats within the α-chain mediate interactions with a variety of extracellular ligands, allowing LRP1 to play a part in a wide variety of cellular processes ranging from homeostasis to cellular signal transduction and even be involved in neurodegenerative diseases. Recently, studies have identified tau as a ligand for LRP1, further implicating LRP1 involvement in neurodegenerative disease. Tau is a microtubule-associated protein whose aggregated form has been linked to Alzheimer’s disease. Despite evidence of the tau-LRP1 interaction, the tau-LRP1 binding mechanism has remained elusive. We first explored whether tau(1n4r) would bind to three complement repeat fragment from the fourth LDL receptor region (sLRP4). When no binding was observed, we prepared the entire sLRP4 using the P. pastoris expression system. Binding of 1n4r to sLRP4 surprisingly resulted in fragmentation of 1n4r. We are currently mapping the fragmentation sites using mass spectrometry and determining the mechanism of fragmentation. Shedding light on the interaction between LRP1 and tau will prove beneficial in understanding underlying mechanisms of LRP1 and development of tau associated neurodegenerative diseases.