Synthesis of High Titer Infectious Prions with Cofactor Molecules

Surachai Supattapone

doi:10.1074/jbc.r113.511329

Abstract

Recently, synthetic prions with a high level of specific infectivity have been produced from chemically defined components in vitro. A major insight arising from these studies is that various classes of host-encoded cofactor molecules such as phosphatidylethanolamine and RNA molecules are required to form and maintain the specific conformation of infectious prions. Synthetic mouse prions formed with phosphatidylethanolamine exhibit levels of specific infectivity ∼1 million-fold greater than "protein-only" prions (Deleault, N. R., Walsh, D. J., Piro, J. R., Wang, F., Wang, X., Ma, J., Rees, J. R., and Supattapone, S. (2012) Proc. Natl. Acad. Sci. U.S.A. 109, E1938-E1946). Moreover, cofactor molecules also appear to regulate prion strain properties by limiting the potential conformations of the prion protein (see Deleault et al. above). The production of fully infectious synthetic prions provides new opportunities to study the mechanism of prion infectivity directly by structural and biochemical methods.

Highlights

Several lines of evidence indicate that prion infectivity and strain properties are encoded by specific PrPSc conformation(s), but at present neither the tertiary structure of infectious PrPSc nor the molecular mechanism responsible for generating
Studies of infectious prion propagation in vitro have highlighted the important role played by cofactor molecules in this process
Cofactor molecules appear to help maintain the infectious conformation of PrPSc and may influence strain properties by facilitating specific PrPSc conformation(s)

Summary

Synthesis of High Titer Infectious Prions with Cofactor Molecules*

Surachai Supattapone From the Departments of Biochemistry and Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755. A major insight arising from these studies is that various classes of host-encoded cofactor molecules such as phosphatidylethanolamine and RNA molecules are required to form and maintain the specific conformation of infectious prions. The production of fully infectious synthetic prions provides new opportunities to study the mechanism of prion infectivity directly by structural and biochemical methods. Several lines of evidence indicate that prion infectivity and strain properties are encoded by specific PrPSc conformation(s), but at present neither the tertiary structure of infectious PrPSc nor the molecular mechanism responsible for generating. The insights provided by these studies have enabled the efficient synthesis of high titer infectious prions from chemically defined components in vitro, an advance that should facilitate experimental determination of the tertiary structure of PrPSc by biophysical techniques such as solid-state nuclear magnetic resonance

In Vitro Formation of PrPSc and Prion Infectivity

Identification of Endogenous PrPSc Propagation Cofactors

Essential Role of Cofactor for Maintaining Infectious PrPSc Conformation

Strain Properties of Synthetic Prions

Conclusions and Future Prospects