Interaction of Peptide Aptamers with Prion Protein Central Domain Promotes α-Cleavage of PrPC.

Abstract

Prion diseases are infectious and fatal neurodegenerative diseases affecting humans and animals. Transmission is possible within and between species with zoonotic potential. Currently, no prophylaxis or treatment exists. Prions are composed of the misfolded isoform PrPSc of the cellular prion protein PrPC. Expression of PrPC is a prerequisite for prion infection, and conformational conversion of PrPC is induced upon its direct interaction with PrPSc. Inhibition of this interaction can abrogate prion propagation, and we have previously established peptide aptamers (PAs) binding to PrPC as new anti-prion compounds. Here, we mapped the interaction site of PA8 in PrP and modeled the complex in silico to design targeted mutations in PA8 which presumably enhance binding properties. Using these PA8 variants, we could improve PA-mediated inhibition of PrPSc replication and de novo infection of neuronal cells. Furthermore, we demonstrate that binding of PA8 and its variants increases PrPC α-cleavage and interferes with its internalization. This gives rise to high levels of the membrane-anchored PrP-C1 fragment, a transdominant negative inhibitor of prion replication. PA8 and its variants interact with PrPC at its central and most highly conserved domain, a region which is crucial for prion conversion and facilitates toxic signaling of Aβ oligomers characteristic for Alzheimer's disease. Our strategy allows for the first time to induce α-cleavage, which occurs within this central domain, independent of targeting the responsible protease. Therefore, interaction of PAs with PrPC and enhancement of α-cleavage represent mechanisms that can be beneficial for the treatment of prion and other neurodegenerative diseases.

• Authors: Erica Corda, Xiaotang Du, Su Yeon Shim, Antonia N Klein, Jessica Siltberg-Liberles, Sabine Gilch
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 55 Issue 10 Pg. 7758-7774 (Oct 2018) ISSN: 1559-1182 [Electronic] United States
• PMID: 29460268 (Publication Type: Journal Article)

Chemical References

• Aptamers, Peptide
• Mutant Proteins
• PrPC Proteins
• Thioredoxins

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Aptamers, Peptide (chemistry, metabolism)
• Binding Sites
• Cell Line, Tumor
• Computer Simulation
• Humans
• Mice
• Mutant Proteins (metabolism)
• PrPC Proteins (chemistry, metabolism)
• Protein Binding
• Protein Domains
• Thioredoxins (metabolism)