The prion protein is embedded in a molecular environment that modulates transforming growth factor β and integrin signaling

Farinaz Ghodrati^1,2, Mohadeseh Mehrabian¹, Declan Williams¹, Gerold Schmitt-Ulms^1,2*

¹Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada; ²Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

*Corresponding Author

At times, it can be difficult to discern if a lack of overlap in reported interactions for a protein-of-

interest reflects differences in methodology or biology. A case in point is the prion protein

(PrP), best known for its central role in prion disorders. In such instances, systematic analyses of protein-protein networks across diverse paradigms can provide valuable insights. Here, we interrogated the PrP interactome in four mouse cell lines. Analyses made use of identical affinity capture and sample processing workflows. Negative controls were generated from PrP knockout lines of the respective cell models, and the relative levels of peptides were quantified with the help of isobaric labels. The study uncovered 26 proteins, which reside in proximity to PrP. All of these proteins are predicted to have access to the outer face of the plasma membrane, and approximately half of them were not reported to interact with PrP before. Strikingly, although several proteins exhibited profound co-enrichment with PrP in a given model, except for Neural Cell Adhesion Molecule 1 (NCAM1), no protein was highly enriched in all four PrP-specific interactomes. A majority of proteins that co-purified with PrP are known to play roles in epithelial-to-mesenchymal transition (EMT), either by acting as transforming growth factor β (TGF-β) signaling modulators, through facilitating the formation of NCAM1-dependent focal adhesion complexes, or by mediating integrin-mediated downstream cell signaling.

Funding Acknowledgements: Rosiak Borden Fund

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