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Mutations and Natural Selection in the Protein World
doi:10.1016/j.jmb.2011.08.013
J. Mol. Biol. (2011) 413, 525–526 Contents lists available at www.sciencedirect.com
Journal of Molecular Biology j o u r n a l h o m e p a g e : h t t p : / / e e s . e l s e v i e r. c o m . j m b
COMMENTARY
Mutations and Natural Selection in the Protein World In this issue of Journal of Molecular Biology, Ghaemmaghami et al. from the laboratory of S. Prusiner report on the variability and natural selection of protein-based infectious agents (prions). 1 The heritable change (mutation) of the nucleic acid sequence template, followed by natural selection of the mutant variants, provides a cornerstone for biological evolution. Conventional wisdom, espoused by most biological textbooks, implies that an analysis of DNA variations is sufficient for uncovering the evolutionary history of a species. However, this view is challenged by the existence of prions, infectious or heritable units that lack nucleic acids and are composed solely of proteins. Mammalian prion protein (PrP) is associated with transmissible spongiform encephalopathies in mammals and humans (e.g., scrapie, “mad cow” disease and Creutzfeldt–Jacob disease); 2 however, it is now clear that many proteins from different organisms possess prion properties. 3,4 The best-understood examples of prions represent conformational derivatives of normal proteins that are maintained as non-covalent polymers (amyloids). They reproduce themselves by immobilizing a normal protein of the same sequence into a polymer and then convert it into a prion conformation. Thus, the protein conformation serves as a structural template. To complicate matters further, a protein of one and the same sequence can produce different structural variants or “strains”. 5,6 Once formed, each strain is faithfully reproduced in the process of prion proliferation. Are, then, proteinbased structural templates capable of mutating and becoming a subject of natural selection, similar to DNA-based genes? A work by Ghaemmaghami et al., confirms that prions indeed undergo mutations and are under the pressure of natural selection, resulting in preferential survival of strains that are best adapted to specific conditions. 1 The authors produced an initial prion by polymerizing a synthetic mouse prion protein (PrP) in a test tube, followed by infection into the mouse. During adaptation of the synthetic prion to the mammalian host, a new prion strain
that was characterized by a lower physical stability but an increased ability to proliferate in the host organism was selected. Different prion strains could be “cloned” and faithfully maintained by infecting cultured cells; however, one strain outcompeted another in cases of mixed infection. Notably, the selection process was modulated by culture conditions and some chemicals. Results of Ghaemmaghami et al. 1 echo a previous publication by Li et al. 7 from the laboratory of C. Weissmann who demonstrated that different prion strains could be selected from the same stock upon transfer from brains to cultured cells and back or after exposure to the inhibitor swansonine. Mutations of cervid prions in brain extracts from different hosts were also reported by Angers et al. 8 However, Ghaemmaghami et al. add that synthetically produced prions become a target of selection after introduction into organisms and establish a reverse correlation between the prion physical stability and efficient proliferation in vivo that partly explains differences in vectors of selection. 1 Molecular mechanisms underlying protein mutations remain to be determined. Some insight could be provided by yeast models. In yeast, a reverse correlation between prion proliferation and physical stability was detected because the more efficient fragmentation of prion polymers produces a larger number of new proliferating units. 9,10 “Mutations” of yeast prion strains were obtained after transmission of the prion conformation to a homologous protein of a divergent sequence (originated from a different species), followed by the subsequent return to the protein of the original sequence. 11 This resembles the “strain adaptation” phenomenon described in mammals. 12,13 Remarkably, the same regions of the prion domain controlled both the efficiency of cross-species prion transmission and the fidelity of reproduction of the strain-specific properties during cross-species transmission in yeast. 11 Altogether, these data show that the key in understanding protein mutations lies in deciphering protein–protein interactions involved in the generation and stabilization of a prion conformation.
0022-2836/$ - see front matter © 2011 Elsevier Ltd. All rights reserved.
526 Whatever is the code of structural templating, its existence and importance can no longer be ignored in studies of infection, heredity and evolution. Moreover, prion-like features of various human protein assembly disorders 14 and biological effects associated with some amyloids 3,15 show that we are dealing with a phenomenon of broad biological and clinical importance, having potential implications well beyond a few infectious diseases.
References 1. Ghaemmaghami, S., Watts, J., Nguyen, H. O., Hayashi, S., DeArmond, S. J. & Prusiner, S. B. (2011). Conformational transformation and selection of synthetic prion strains. J. Mol. Biol. (this issue). 2. Weissmann, C. (2004). The state of the prion. Nat. Rev., Microbiol. 2, 861–871. 3. Halfmann, R. & Lindquist, S. (2010). Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits. Science, 330, 629–632. 4. Wickner, R. B., Shewmaker, F., Kryndushkin, D. & Edskes, H. K. (2008). Protein inheritance (prions) based on parallel in-register β-sheet amyloid structures. BioEssays, 30, 955–964. 5. Dickinson, A. G. & Meikle, V. M. H. (1969). A comparison of some biological characteristics of the mouse-passaged scrapie agents, 22A and ME7. Genet. Res. 13, 213–225. 6. Bessen, R. A. & Marsh, R. F. (1994). Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J. Virol. 68, 7859–7868. 7. Li, J., Browning, S., Mahal, S. P., Oelschlegel, A. M. & Weissmann, C. (2009). Darwinian evolution of prions in cell culture. Science, 327, 869–872.
Protein Mutations and Selection 8. Angers, R. C., Kang, H. E., Napier, D., Browning, S., Seward, T., Mathiason, C. et al. (2010). Prion strain mutation determined by prion protein conformational compatibility and primary structure. Science, 328, 1154–1158. 9. Tanaka, M., Collins, S. R., Toyama, B. H. & Weissman, J. S. (2006). The physical basis of how prion conformations determine strain phenotypes. Nature, 442, 585–589. 10. Cox, B. S., Byrne, L. J. & Tuite, M. F. (2007). Prion stability. Prion, 1, 170–178. 11. Chen, B., Bruce, K. L., Newnam, G. P., Gyoneva, S., Romanyuk, A. V. & Chernoff, Y. O. (2010). Genetic and epigenetic control of the efficiency and fidelity of cross-species prion transmission. Mol. Microbiol. 6, 1483–1499. 12. Kimberlin, R. H. & Walker, C. A. (1986). Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J. Gen. Virol. 67, 255–263. 13. Scott, M., Foster, D., Mirenda, C., Serban, D., Coufal, F., Wälchli, M. et al. (1989). Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell, 59, 847–857. 14. Aguzzi, A. & Rajendran, L. (2009). Transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron, 64, 783–790. 15. Inge-Vechtomov, S. G., Zhouravleva, G. A. & Chernoff, Y. O. (2007). Biological roles of prion domains. Prion, 1, 228–235.
Yury O. Chernoff School of Biology, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, GA 30332-0230, USA E-mail address: [email protected].
J. Mol. Biol. (2011) 413, 525–526 Contents lists available at www.sciencedirect.com
Journal of Molecular Biology j o u r n a l h o m e p a g e : h t t p : / / e e s . e l s e v i e r. c o m . j m b
COMMENTARY
Mutations and Natural Selection in the Protein World In this issue of Journal of Molecular Biology, Ghaemmaghami et al. from the laboratory of S. Prusiner report on the variability and natural selection of protein-based infectious agents (prions). 1 The heritable change (mutation) of the nucleic acid sequence template, followed by natural selection of the mutant variants, provides a cornerstone for biological evolution. Conventional wisdom, espoused by most biological textbooks, implies that an analysis of DNA variations is sufficient for uncovering the evolutionary history of a species. However, this view is challenged by the existence of prions, infectious or heritable units that lack nucleic acids and are composed solely of proteins. Mammalian prion protein (PrP) is associated with transmissible spongiform encephalopathies in mammals and humans (e.g., scrapie, “mad cow” disease and Creutzfeldt–Jacob disease); 2 however, it is now clear that many proteins from different organisms possess prion properties. 3,4 The best-understood examples of prions represent conformational derivatives of normal proteins that are maintained as non-covalent polymers (amyloids). They reproduce themselves by immobilizing a normal protein of the same sequence into a polymer and then convert it into a prion conformation. Thus, the protein conformation serves as a structural template. To complicate matters further, a protein of one and the same sequence can produce different structural variants or “strains”. 5,6 Once formed, each strain is faithfully reproduced in the process of prion proliferation. Are, then, proteinbased structural templates capable of mutating and becoming a subject of natural selection, similar to DNA-based genes? A work by Ghaemmaghami et al., confirms that prions indeed undergo mutations and are under the pressure of natural selection, resulting in preferential survival of strains that are best adapted to specific conditions. 1 The authors produced an initial prion by polymerizing a synthetic mouse prion protein (PrP) in a test tube, followed by infection into the mouse. During adaptation of the synthetic prion to the mammalian host, a new prion strain
that was characterized by a lower physical stability but an increased ability to proliferate in the host organism was selected. Different prion strains could be “cloned” and faithfully maintained by infecting cultured cells; however, one strain outcompeted another in cases of mixed infection. Notably, the selection process was modulated by culture conditions and some chemicals. Results of Ghaemmaghami et al. 1 echo a previous publication by Li et al. 7 from the laboratory of C. Weissmann who demonstrated that different prion strains could be selected from the same stock upon transfer from brains to cultured cells and back or after exposure to the inhibitor swansonine. Mutations of cervid prions in brain extracts from different hosts were also reported by Angers et al. 8 However, Ghaemmaghami et al. add that synthetically produced prions become a target of selection after introduction into organisms and establish a reverse correlation between the prion physical stability and efficient proliferation in vivo that partly explains differences in vectors of selection. 1 Molecular mechanisms underlying protein mutations remain to be determined. Some insight could be provided by yeast models. In yeast, a reverse correlation between prion proliferation and physical stability was detected because the more efficient fragmentation of prion polymers produces a larger number of new proliferating units. 9,10 “Mutations” of yeast prion strains were obtained after transmission of the prion conformation to a homologous protein of a divergent sequence (originated from a different species), followed by the subsequent return to the protein of the original sequence. 11 This resembles the “strain adaptation” phenomenon described in mammals. 12,13 Remarkably, the same regions of the prion domain controlled both the efficiency of cross-species prion transmission and the fidelity of reproduction of the strain-specific properties during cross-species transmission in yeast. 11 Altogether, these data show that the key in understanding protein mutations lies in deciphering protein–protein interactions involved in the generation and stabilization of a prion conformation.
0022-2836/$ - see front matter © 2011 Elsevier Ltd. All rights reserved.
526 Whatever is the code of structural templating, its existence and importance can no longer be ignored in studies of infection, heredity and evolution. Moreover, prion-like features of various human protein assembly disorders 14 and biological effects associated with some amyloids 3,15 show that we are dealing with a phenomenon of broad biological and clinical importance, having potential implications well beyond a few infectious diseases.
References 1. Ghaemmaghami, S., Watts, J., Nguyen, H. O., Hayashi, S., DeArmond, S. J. & Prusiner, S. B. (2011). Conformational transformation and selection of synthetic prion strains. J. Mol. Biol. (this issue). 2. Weissmann, C. (2004). The state of the prion. Nat. Rev., Microbiol. 2, 861–871. 3. Halfmann, R. & Lindquist, S. (2010). Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits. Science, 330, 629–632. 4. Wickner, R. B., Shewmaker, F., Kryndushkin, D. & Edskes, H. K. (2008). Protein inheritance (prions) based on parallel in-register β-sheet amyloid structures. BioEssays, 30, 955–964. 5. Dickinson, A. G. & Meikle, V. M. H. (1969). A comparison of some biological characteristics of the mouse-passaged scrapie agents, 22A and ME7. Genet. Res. 13, 213–225. 6. Bessen, R. A. & Marsh, R. F. (1994). Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J. Virol. 68, 7859–7868. 7. Li, J., Browning, S., Mahal, S. P., Oelschlegel, A. M. & Weissmann, C. (2009). Darwinian evolution of prions in cell culture. Science, 327, 869–872.
Protein Mutations and Selection 8. Angers, R. C., Kang, H. E., Napier, D., Browning, S., Seward, T., Mathiason, C. et al. (2010). Prion strain mutation determined by prion protein conformational compatibility and primary structure. Science, 328, 1154–1158. 9. Tanaka, M., Collins, S. R., Toyama, B. H. & Weissman, J. S. (2006). The physical basis of how prion conformations determine strain phenotypes. Nature, 442, 585–589. 10. Cox, B. S., Byrne, L. J. & Tuite, M. F. (2007). Prion stability. Prion, 1, 170–178. 11. Chen, B., Bruce, K. L., Newnam, G. P., Gyoneva, S., Romanyuk, A. V. & Chernoff, Y. O. (2010). Genetic and epigenetic control of the efficiency and fidelity of cross-species prion transmission. Mol. Microbiol. 6, 1483–1499. 12. Kimberlin, R. H. & Walker, C. A. (1986). Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J. Gen. Virol. 67, 255–263. 13. Scott, M., Foster, D., Mirenda, C., Serban, D., Coufal, F., Wälchli, M. et al. (1989). Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell, 59, 847–857. 14. Aguzzi, A. & Rajendran, L. (2009). Transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron, 64, 783–790. 15. Inge-Vechtomov, S. G., Zhouravleva, G. A. & Chernoff, Y. O. (2007). Biological roles of prion domains. Prion, 1, 228–235.
Yury O. Chernoff School of Biology, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, GA 30332-0230, USA E-mail address: [email protected].