Interactome Analyses Identify Ties of PrPC and Its Mammalian Paralogs to Oligomannosidic N-Glycans and Endoplasmic Reticulum-Derived Chaperones

PLoS Pathogens

Lei Xu¹  George A. Carlson¹  Joel C. Watts²  Nathalie Daude²  Rebecca Young²  Yu Bai²  Amy Hye Won²  Sepehr Ehsani²  Agnes Lau³  Hairu Huo³  Tujin Shi³  David Williams⁴  Gerold Schmitt-Ulms⁴  David Westaway⁴ 

[1] Alberta Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada;Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada;Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;McLaughlin Research Institute, Great Falls, Montana, United States of America

关键词: Membrane proteins;    Chaperone proteins;    Cell membranes;    Prion diseases;    Adhesion molecules;    Isomerases;    Protein domains;    Protein interactions;   

DOI  :  10.1371/journal.ppat.1000608

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The physiological environment which hosts the conformational conversion of the cellular prion protein (PrPC) to disease-associated isoforms has remained enigmatic. A quantitative investigation of the PrPC 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 PrPC 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 PrPC 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 PrPC with PDIs may extend beyond the endoplasmic reticulum and may play a hitherto unrecognized role in the accumulation of PrPSc. A simple hypothesis is presented which accounts for the majority of interactions observed in uninfected cells and suggests that PrPC 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.

【 授权许可】

CC BY