Neurobiology of Alzheimer's Disease - Guojun Bu

The LDL Receptor Family: Biogenesis, Endocytic Trafficking and Signaling

More than 10 receptors have now been identified as members of the low-density lipoprotein receptor (LDLR) family; they all contain characteristic ligand-binding repeats, epidermal growth factor (EGF)-like repeats and propeller-like structures with YWTD motifs.

These receptors bind a diverse array of ligands, including apolipoprotein E (apoE) and amyloid precursor protein (APP), to mediate their transport and/or signaling. A unique feature of low-density lipoprotein receptor-related protein 1 (LRP1) endocytic trafficking is its rapid endocytosis, which is mediated by several endocytosis signals, including an YXXL motif, a dileucine motif and a protein kinase A (PKA)-mediated phosphorylation of a serine residue.¹ The lab has also found that a cytosolic adaptor protein, sorting nexin 17, interacts with the first NPXY motif of LRP1 tail and regulates its recycling.²

Studies in Dr. Bu's laboratory have focused on understanding how LDLR family members traffic within cells and how their biological functions are regulated by these trafficking events. In addition to LRP1, the lab is also studying low-density lipoprotein receptor-related protein 1B (LRP1B) and low-density lipoprotein receptor-related protein 6 (LRP6) trafficking, signaling and functions. LRP1B is a putative tumor suppressor that is highly homologous to LRP1. LRP6 is a co-receptor for canonical Wnt/beta-catenin signaling.³

Additionally, the lab has been studying how two chaperones, receptor-associated protein (RAP) and MESD, regulate the complex folding of LDLR family members and their biological functions.

References

• Li Y, Marzolo MP, van Kerkhof P, Strous GJ, Bu G. The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. J Biol Chem. 2000 Jun 2;275(22):17187-94. PMID: 10747918
• van Kerkhof P, Lee J, McCormick L, Tetrault E, Lu W, Schoenfish M, Oorschot V, Strous GJ, Klumperman J, Bu G. Sorting nexin 17 facilitates LRP recycling in the early endosome. EMBO J. 2005 Aug 17;24(16):2851-61. PMID: 16052210
• Liu CC, Pearson C, Bu G. Cooperative folding and ligand-binding properties of LRP6 beta-propeller domains. J Biol Chem. 2009 May 29;284(22):15299-307. PMID: 19339249