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

• Published in: The Journal of biological chemistry 2010-06, Vol.285 (26), p.20213-20223
• Main Authors: Harrison, Christopher F., Lawson, Victoria A., Coleman, Bradley M., Kim, Yong-Sun, Masters, Colin L., Cappai, Roberto, Barnham, Kevin J., Hill, Andrew F.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Amyloid; Animals; Brain - metabolism; Brain - pathology; Cell Line; Glycine - genetics; Glycine - metabolism; GXXXG Motif; Hydrophobic and Hydrophilic Interactions; Hydrophobic Domain; Lipid Raft; Membrane Microdomains - metabolism; Mice; Microscopy, Fluorescence; Molecular Bases of Disease; Molecular Sequence Data; Mutation; Neurodegeneration; Neurological Diseases; Prions; Protein Binding; Protein Folding; Protein Motifs; PrPC Proteins - chemistry; PrPC Proteins - genetics; PrPC Proteins - metabolism; PrPSc Proteins - chemistry; PrPSc Proteins - genetics; PrPSc Proteins - metabolism; Sequence Homology, Amino Acid; Transfection; Transmissible Spongiform Encephalopathy
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.093310

Prion diseases are associated with the misfolding of the endogenously expressed prion protein (designated PrPC) into an abnormal isoform (PrPSc) that has infectious properties. The hydrophobic domain of PrPC 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 PrPC. Mutagenesis studies demonstrate that minor alterations to this highly conserved region of PrPC drastically affect the ability of cells to uptake and replicate prion infection in both cell and animal bioassay. The localization and processing of mutant PrPC are not affected, although in vitro and in vivo studies demonstrate that this region is not essential for interaction with PrPSc, suggesting these residues provide conformational flexibility. These data suggest that this region of PrPC is critical in the misfolding process and could serve as a novel, species-independent target for prion disease therapeutics.