Conservation of a Glycine-rich Region in the Prion Protein Is Required for Uptake of Prion Infectivity

Abstract

Prion diseases are associated with the misfolding of the endogenously expressed prion protein (designated PrP C ) into an abnormal isoform (PrP Sc ) that has infectious properties. The hydrophobic domain of PrP C is highly conserved and contains a series of glycine residues that show perfect conservation among all species, strongly suggesting it has functional and evolutionary significance. These glycine residues appear to form repeats of the GXXXG protein-protein interaction motif (two glycines separated by any three residues); the retention of these residues is significant and presumably relates to the functionality of PrP C . Mutagenesis studies demonstrate that minor alterations to this highly conserved region of PrP C drastically affect the ability of cells to uptake and replicate prion infection in both cell and animal bioassay. The localization and processing of mutant PrP C are not affected, although in vitro and in vivo studies demonstrate that this region is not essential for interaction with PrP Sc , suggesting these residues provide conformational flexibility. These data suggest that this region of PrP C is critical in the misfolding process and could serve as a novel, species-independent target for prion disease therapeutics.

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

“…This region (residues 268 to 315) is particularly glycine rich (Fig. 8a), with multiple putative GXXXG motifs; these motifs are believed to mediate hydrophobic helical protein-protein interactions and have also been found in other proteins involved in neurodegenerative disorders (13,40). We should also note that while sorbitol can be an oxidative stressor (Fig.…”

Stimulating the Release of Exosomes Increases the Intercellular Transfer of Prions

“…Confocal Microscopy-Cells were prepared for confocal microscopy as described previously with modifications (30). Cells were seeded into 8-well Slide chamber slides (iBidi GmbH, Martinsried, Germany) and allowed to attach overnight.…”

Mouse Prion Protein (PrP) Segment 100 to 104 Regulates Conversion of PrP C to PrP Sc in Prion-Infected Neuroblastoma Cells

“…In screening assays utilizing MoPrP-derived peptide libraries grafted into immunoglobulin G molecules, the peptides corresponding to residues 23 to 33, 97 to 109, and 135 to 157 of MoPrP strongly bound to PrP Sc (29,30,48 (35), and 218 to 232 (18) of MoPrP or the amino acid substitution at residue 138 (37) interfered with the propagation of PrP Sc . However, the incubation of prion-infected cells (RK13 cells) with the 1C5 antibody against residues 118 to 129 of MoPrP (7) for a week was ineffective at reducing the accumulation of PrP Sc in the cells (16). We consider that the dominant and highaffinity binding interface for PrP…”