Professor, Biochemistry and Molecular Biology; Dean, College of Natural Sciences
PhD: Yale University
Postdoc: The University of Chicago
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.
Langlois, C.R., Pei, F., Sindi, S.S., and Serio, T.R. (2016). Distinct Prion Domain Sequences Ensure Efficient Amyloid Propagation by Promoting Chaperone Binding or Processing In Vivo. PLoS Genet. 12(11), e1006417.
Pezza, J.A., Villali, J., Sindi, S.S., and Serio, T.R. (2014). Amyloid-associated activity contributes to the severity and toxicity of a prion phenotype. Nat. Commun. 5, 4384.
Klaips, C.L., Hochstrasser, M.L., Langlois, C.R., and Serio, T.R. (2014). Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing. Elife 3, e04288.
Holmes, W.M., Mannakee, B.K., Gutenkunst, R.N., and Serio, T.R.(2014). Loss of amino-terminal acetylation suppresses a prion phenotype by modulating global protein folding. Nat. Commun. 5, 4383.
Holmes, W.M., Klaips, C.L., and Serio, T.R. (2014). Defining the limits: Protein aggregation and toxicity in vivo. Crit. Rev. Biochem. Mol. Biol. 49, 294–303.
DiSalvo, S., Derdowski, A., Pezza, J.A., and Serio, T.R. (2011). Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation. Nat. Struct. Mol. Biol. 18, 486–492.
DiSalvo, S., and Serio, T.R. (2011). Insights into prion biology: Integrating a protein misfolding pathway with its cellular environment. Prion 5, 76–83.
Tuite, M.F., and Serio, T.R. (2010). The prion hypothesis: from biological anomaly to basic regulatory mechanism. Nat. Rev. Mol. Cell Biol. 11, 823–833.
Derdowski, A., Sindi, S.S., Klaips, C.L., DiSalvo, S., and Serio, T.R.(2010). A size threshold limits prion transmission and establishes phenotypic diversity. Science 330, 680–683.
Sindi, S.S., and Serio, T.R. (2009). Prion dynamics and the quest for the genetic determinant in protein-only inheritance. Curr. Opin. Microbiol. 12, 623–630.
Pezza, J.A., Langseth, S.X., Raupp Yamamoto, R., Doris, S.M., Ulin, S.P., Salomon, A.R., and Serio, T.R. (2009). The NatA acetyltransferase couples Sup35 prion complexes to the [PSI+] phenotype. Mol. Biol. Cell 20, 1068–1080.
Pezza, J.A., and Serio, T.R. (2007). Prion Propagation, The Role of Protein Dynamics. Prion 1, 36–43.
Satpute-Krishnan, P., Langseth, S.X., and Serio, T.R. (2007). Hsp104-dependent remodeling of prion complexes mediates protein-only inheritance. PLoS Biol. 5, e24.
Satpute-Krishnan, P., and Serio, T.R. (2005). Prion protein remodelling confers an immediate phenotypic switch. Nature 437, 262–265.