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

Abstract

Low-density lipoprotein receptor-related protein-1 (LRP1) functions as a receptor for nonpathogenic cellular prion protein (PrP C ), which is released from cells by ADAM ( a d isintegrin a nd m etalloproteinase domain) 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 LPS-elicited cytokine expression in macrophages and microglia and rescued the heightened sensitivity to LPS in mice in which the PrP C gene ( Prnp ) had been 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 Lys 100 and Lys 103 into Ala eliminated the activity of P3, suggesting that these residues are essential in the LRP1-binding motif. A P3 derivative in which Lys 105 and Lys 109 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.

LRP1 and p75 Neurotrophin Receptor Collaborate to Trigger Pro-inflammatory Cell-signaling in Response to Extracellular Tau

“…Mice in which macrophages are LRP1-deficient were obtained by breeding Lrp1 flox/flox mice with mice express Cre recombinase under the control of the lysozyme-M (LysM-Cre) promoter, in the C57BL/6J background, as previously described (Overton et al, 2007;Staudt et al, 2013;Mantuano et al, 2016). To generate mice in which macrophages are deficient in the essential NMDA-R GluN1 subunit, Grin1 flox/flox mice were bred with mice that express Cre recombinase under the control of the LysM-Cre promoter in the C57BL/6J background (Mantuano et al, 2023). All research protocols involving mice were approved by the University of California San Diego Institutional Animal Care and Use Committee.…”

“…Next, we isolated NMDA-R-deficient BMDMs from mice in which the gene encoding the essential GluN1 subunit (Grin1) is deleted under the control of the LysM promoter (Mantuano et al, 2023). BMDMs from these mice fail to respond to S-PrP C (Mantuano et al, 2023). However, as shown in Fig.…”

Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases

“…Apart from neurodegenerative conditions, recent studies on potential biological roles of sPrP suggest it to act as a ligand inducing effects in different recipient cell types, regulating cellular differentiation, homeostasis, morphogenesis and immunological processes 45–49 . Depending on the pathophysiological context, sPrP may also play detrimental roles as suggested by studies linking it with elevated inflammatory responses in HIV neuropathogenesis 50 as well as trophic effects or drug-resistance in cancer 51,52 .…”