Tricia Serio, Ph.D.Edit My Page
In a variety of systems, proteins have been linked to processes historically limited to nucleic acids, such as infectivity and inheritance. Such proteins, termed prions, adopt multiple physical and therefore functional states in vivo, an attribute underlying their atypical roles in the cell. Our work seeks to elucidate the molecular mechanisms that module prion protein conformational flexibility in vivo using the yeast Saccharomyces cerevisiae as an experimental model.
Professor Serio received her B.S. in Molecular Biology from Lehigh University in 1991 and completed her graduate work in Molecular Biochemistry and Biophysics as a fellow of the Howard Hughes Medical Institute at Yale University (M.Phil 1995, Ph.D. 1997). From 1997 through 2002, she was a post-doctoral fellow of the Damon Runyon-Walter Winchell Cancer Research Fund at the University of Chicago and a recipient of the Howard Temin Award from the National Cancer Institute at Yale University. She joined the faculty at Brown University as an assistant professor in 2002 and was promoted to associate professor in 2008. Her research focuses on self-perpetuating protein conformations in the yeast Saccharomyces cerevisiae as model for severe neurodegenerative diseases in mammals.
A protein's activity is a direct manifestation of its structure, and the cell expends considerable energy to ensure that a nascent protein efficiently adopts a single, correct three-dimensional fold. In theory, the road map from synthesis to functional form is specified by the protein's primary sequence of amino acids, but in practice, nascent proteins frequently misfold into alternate conformations. In most instances, cells recognize these aberrant forms and target them to molecular chaperones for refolding or to proteases for destruction. However, a group of proteins known as prions is an exception to these rules. Prions have the capacity to adopt multiple stable forms in vivo, and, since a protein's structure determines its function, cells containing the same protein in two different conformations will have different phenotypes. For instance, one conformation of the mammalian prion protein PrP is non-pathogenic, while other forms likely mediate the development of severe neurodegenerative disease (e.g., mad cow disease, Creutzfeldt-Jacob Disease, kuru). Remarkably, some of these diseases are infectious, suggesting that the aberrant protein conformations are acting as genetic elements, a role historically limited to nucleic acids.
How do prion proteins act in these atypical roles? A fine-tuned regulation of prion protein structural flexibility is key. If each newly synthesized molecule of a prion protein could independently choose between forms, all cells would display a single phenotype that is the average of the two states. The appearance of distinct phenotypes in vivo suggests that while the prion protein remains flexible enough to access multiple forms, its folding is somehow constrained in any given cell such that only one form persists.
Our current work seeks to elucidate the molecular mechanisms underlying the near-faithful propagation of prion forms in vivo using the Sup35/[PSI+] prion of Saccharomyces cerevisiae as an experimental model.
Howard Temin Award
Pew Scholar in the Biomedical Sciences
Prion Cycle Regulation In Vivo
NIH/NIGMS (R01 GM069802-01)
Principal Investigator: Tricia Serio
Prion Dynamics and Protein-only Inheritance
Principal Investigator: Tricia Serio
- Advanced Biochemistry (BIOL1270)
- Foundations for Advanced Study in Experimental Biology (BIOL2030)
- Scientific Communication (BIOL2150)
- DiSalvo, S., Derdowski, A., Pezza, J.A., and Serio T.R. Dominant Prion Mutants Induce Curing Through Pathways That Promote Chaperone-Mediated Degradation. Nat Struct Mol Biol 18:486-92 (2011).(2011)
- Derdowski, A., Sindi S.S., Klaips, C.L., DiSalvo, S. and Serio T.R. A Size Threshold Limits Prion Transmission and Establishes Phenotypic Diversity. Science 330:680-3 (2010).(2010)
- Tuite, M.F. and Serio T.R. The Prion Hypothesis: From Biological Anomaly to Basic Regulatory Mechanism. Nat Rev Mol Cell Biol 11:823-33 (2010).(2010)
- Pezza J.A., Langseth S.X., Yamamoto R.R., Doris S.M., Ulin S.P., Salomon A.R., and Serio T.R. The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI+] Phenotype. Mol Biol Cell 20:1068-80 (2009).(2009)
- Sindi S.S. and Serio T. R. Prion Dynamics and the Quest for the Genetic Determinant in Protein-Only Inheritance. Current Opinion in Microbiology 12:623-30 (2009)(2009)
- Satpute-Krishnan P., Langseth S., and Serio T.R. Hsp104-Dependent Remodeling of Prion Complexes Mediates Protein-Only Inheritance. PLoS Biology 5:e24 (2007).(2007)
- Pezza J.A. and Serio T.R. Prion Propagation, The Role of Protein Dynamics. Prion 1: 36-43 (2007).(2007)
- Satpute-Krishnan P and Serio T.R. Prion Protein Remodelling Confers An Immediate Phenotypic Switch. Nature 437: 262-5 (2005).(2005)
- Serio T.R. and Lindquist S.L. The Yeast Prion [PSI+]:Molecular Insights and Functional Consequences. Adv Protein Chem 59:391-412 (2001) .(2001)
- Serio T.R. and Lindquist S.L. [PSI+], Sup35 and Chaperones. Adv Protein Chem 57:335-66 (2001).(2001)
- Serio T.R., Cashikar A.G., Kowal A.S., Sawicki, G., and Lindquist S.L. Self-Perpetuating Changes in Sup35 Protein Conformation as a Mechanism of Heredity in yeast. in Biochem Soc Symp 68:35-43 (2001)(2001)
- (subject of news and views, Nature Structural Biology 7: 824-6 (2000))(2000)
- Serio T.R., Cashikar A.G., Kowal A.S., Sawicki G.J. Moslehi, J.J., Serpell L., Arnsdorf M.F., and Lindquist S.L. Nucleated Conformational Conversion and the Replication of Conformational Information by a Prion Determinant. Science 289:1317-21 (2000)(2000)
- Serio T.R. and Lindquist S.L. Protein-only inheritance in yeast: something to get [PSI+]-ched about. Trends Cell Biol 10:98-105 (2000).(2000)
- Serio T.R. and Lindquist S.L. [PSI+] : An Epigenetic Modulator of Translation Termination Efficiency. Ann Rev Cell Dev Biol 15:661-703 (1999).(1999)
- Serio T.R., Cashikar A.G., Moslehi J.J., Kowal A.S., and Lindquist S.L. Yeast Prion [PSI+] and Its Determinant, Sup35p. Meth Enz 309: 649-673 (1999).(1999)
- Lindquist S., DebBurman S.K., Glover J.R., Kowal A.S., Liu J.J., Schirmer E.C., and Serio T.R. Amyloid fibres of Sup35 support a prion-like mechanism of inheritance in yeast. Biochem Soc Trans 26:486-90 (1998)(1998)