Chaperone Effects on Prion and Nonprion Aggregates

Abstract

Exposure to high temperature or other stresses induces a synthesis of heat shock proteins. Many of these proteins are molecular chaperones, and some of them help cells to cope with heat induced denaturation and aggregation of other proteins. In the last decade, chaperones have received increased attention in connection with their role in maintenance and propagation of the Saccharomyces cerevisiae prions, infectious or heritable agents transmitted at the protein level. Recent data suggest that functioning of the chaperones in reactivation of heat damaged proteins and in propagation of prions is based on the same molecular mechanisms but may lead to different consequences depending on the type of aggregate. In both cases the concerted and balanced action of “chaperones’ team”, including Hsp104, Hsp70, Hsp40 and possibly other proteins, determines whether a misfolded protein is to be incorporated into an aggregate, rescued to the native state or targeted for degradation.

Acknowledgements

This work was supported by grants R01GM58763 from NIH to Yury O. Chernoff and 04-04-48275a from Russian Foundation of Basic Research to Eugene G. Rikhvanov.

Figures and Tables

Figure 1 Structural organization of the yeast Hsp proteins involved in stress protection and prion propagation. (A) Hsp104; (B) Ssa1 as a representative of the Hsp70 family; (C) Hsp40 type I (Ydj1); (D) Hsp40 type II (Sis1). (The Hsp40 type III is not shown.) Designations: NBD, nucleotide-binding domain; NTD, N-terminal domain, middle region; CTD, C-terminal domain; J, J-domain; G/F, glycine and phenylalanine-rich region; Zinc, zinc-finger domain; G/M, glycine and methionine-rich region; DD, dimerization domain; E, glutamic acid; V, valine; D, aspartic acid. Numbers correspond to aa positions.

Figure 2 Model for the role of molecular chaperones in formation and propagation of the [PSI⁺] prion. CSK, cytoskeleton; UPS, ubiquitin-proteasome system; IBs, inclusion bodies. See comments in text.

Note

This manuscript has been previously published: Rikhvanov EG, Romanova NV, Chernoff YO. Chaperone Effects on Prion and Nonprion Aggregates. Protein-Based Inheritence Chernoff Y. Austin and New York Landes Bioscience and Kluwer Academic Press 2007; 83 - 92

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