An LRP1-binding motif in cellular prion protein replicates cell-signaling activities of the full-length protein

Low Density Lipoprotein Receptor-related Protein-1 (LRP1) functions as a receptor for non-pathogenic cellular prion protein (PrP^C), which is released from cells by ADAM proteases or in extracellular vesicles. This interaction activates cell-signaling and attenuates inflammatory responses. We screened 14-mer PrP^C-derived peptides and identified a putative LRP1 recognition motif in the PrP^C sequence spanning residues 98-111. A synthetic peptide (P3) corresponding to this region replicated the cell-signaling and biological activities of full-length shed PrP^C. P3 blocked lipopolysaccharide (LPS)-elicited cytokine expression in macrophages and microglia and rescued the heightened sensitivity to LPS in mice in which the PrP^C gene (Prnp) is deleted. P3 activated ERK1/2 and induced neurite outgrowth in PC12 cells. The response to P3 required LRP1 and the NMDA Receptor and was blocked by the PrP^C-specific antibody, POM2. P3 has Lys residues, which are typically necessary for LRP1-binding. Converting Lys¹⁰⁰ and Lys¹⁰³ into Ala eliminated the activity of P3, suggesting that these residues are essential in the LRP1 binding motif. A P3 derivative in which Lys¹⁰⁵ and Lys¹⁰⁹ were converted into Ala retained activity. We conclude that the biological activities of shed PrP^C, attributed to interaction with LRP1, are retained in synthetic peptides, which may be templates for therapeutics development. 

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