Interactome analyses identify ties of PrP and its mammalian paralogs to oligomannosidic N-glycans and endoplasmic reticulum-derived chaperones.
The physiological environment which hosts the conformational conversion of the cellular prion protein (PrP(C)) to disease-associated isoforms has remained enigmatic. A quantitative investigation of the PrP(C) interactome was conducted in a cell culture model permissive to prion replication. To facilitate recognition of relevant interactors, the study was extended to Doppel (Prnd) and Shadoo (Sprn), two mammalian PrP(C) paralogs. Interestingly, this work not only established a similar physiological environment for the three prion protein family members in neuroblastoma cells, but also suggested direct interactions amongst them. Furthermore, multiple interactions between PrP(C) and the neural cell adhesion molecule, the laminin receptor precursor, Na/K ATPases and protein disulfide isomerases (PDI) were confirmed, thereby reconciling previously separate findings. Subsequent validation experiments established that interactions of PrP(C) with PDIs may extend beyond the endoplasmic reticulum and may play a hitherto unrecognized role in the accumulation of PrP(Sc). A simple hypothesis is presented which accounts for the majority of interactions observed in uninfected cells and suggests that PrP(C) organizes its molecular environment on account of its ability to bind to adhesion molecules harboring immunoglobulin-like domains, which in turn recognize oligomannose-bearing membrane proteins.
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Joel C
JC
Watts
Hairu
H
Huo
Yu
Y
Bai
Sepehr
S
Ehsani
Amy Hye Won
AH
Jeon
Amy Hye
AH
Won
Tujin
T
Shi
Nathalie
N
Daude
Agnes
A
Lau
Rebecca
R
Young
Lei
L
Xu
George A
GA
Carlson
David
D
Williams
David
D
Westaway
Gerold
G
Schmitt-Ulms
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology / Q000379:methods; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D058851:GPI-Linked Proteins; D015870:Gene Expression; D019344:Lactic Acid / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009844:Oligosaccharides / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D014162:Transfection
D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009844:Oligosaccharides; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse; C523856:Sprn protein, mouse; C028569:oligomannoside; D019344:Lactic Acid; D019704:Protein Disulfide-Isomerases