Prions operate outside molecular biology’s central dogma. As protein-based elements
of inheritance, prions perpetuate not by changing the way that genetic information is
transcribed or translated but rather by co-opting the final step in the decoding of
genetic information—protein folding and assembly. The key property of prion-forming
proteins is their ability to assemble into “non-native” structures that then replicate by
coaxing other molecules of the same protein into the structure. The resulting changes
in conformation and cellular localization alter the functions of the proteins involved,
resulting in phenotypes specific to each protein. Consequently, prions dictate not only
the fates of the proteins themselves but also those of the cells and organisms that
We aim to discover new prions and explore how these remarkable elements of
inheritance contribute to phenotypic diversity. Much of our work is performed in
budding yeast, an exceptionally tractable organism that continues to illuminate the
biophysical determinants of prions and the range of phenomena attributable to them. Our recent contributions in this area include the discovery that prions can act as environmentally-responsive epigenetic determinants of cell identity. In particular, prion formation by certain regulatory proteins leads yeast to switch between unicellular and multicellular growth forms. We are now investigating how distinct subpopulations of cells that result from prion switching interact with and influence each other’s fitness. We believe such interactions contribute to the emergence of cooperative intercellular behaviors that characterize phenomena ranging from microbial biofilms to tumor progression.
Prion phenomena derive from universal phase behaviors of polymers. That is, virtually every polypeptide has an intrinsic ability to partition into a nucleated self-interacting phase, which, under permissive physiological conditions, may manifest as a prion.
We contend that prions (per se) are mere escapees of a greater microcosm of nucleated phase transitions that exists within cells, in which protein phase separations serve to encode, amplify, and decode cellular signals. Our recent first explorations of this idea revealed an ancient and highly conserved role for prion-like protein behaviors in innate immune systems. Specifically, certain signaling proteins in both fungi and mammals switch between aqueous and self-templating solid phases in a manner that functionally digitizes cellular responses to pathogenic stimuli. We are now investigating the involvement of this new form of signaling in other pathways and the extent to which it contributes to both normal and pathological processes.
This emerging field presents unique challenges that necessitate a systematic exploration. To do so, we are pioneering a range of assays to detect and quantify protein phase behaviors in living cells. Ultimately, we seek to understand not only the sequence determinants that govern the specificity and thermodynamics of phase transitions, but also how they are regulated by cellular factors and importantly, how we can wield them to the advantage of human health.
Beyond Prions: Molecular Mechanisms of Cooperation
Our observations of social behaviors fostered by prions has piqued our interest in the molecular mechanisms of social evolution. The prevalence of cooperation throughout biology presents a perennial challenge for evolutionary biology, as cooperative phenotypes often directly disadvantage the cooperating individual. Prions are a simple but robust mechanism by which genetically identical individuals can diversify phenotypically. Even if one phenotype is disadvantageous to the individual, it may nevertheless be advantageous to others (for example, through metabolic divisions of labor) and hence to the shared genome. We have discovered that clonal populations of multicellular budding yeast exhibit a rich diversity of cooperative behaviors. We seek to exploit the unparalleled experimental resources available for this organism to yield novel insights into the molecular mechanisms that drive social diversity and evolution.
LABORATORY OPERATIONS MANAGER
Alex Rodriguez Gama
Khan T, Kandola TS, Wu J, Venkatesan S, Ketter E, Lange JJ, Rodriguez Gama A, Box A, Unruh JR, Cook M, Halfmann R. (2018)
Quantifying nucleation in vivo reveals the physical basis of prion-like phase behavior. Mol Cell 71:155-168.e157
Zhang XF, Sun R, Guo Q, Zhang S, Meulia T, Halfmann R, Li D, Qu F. (2017) A self-perpetuating repressive state of a viral replication protein blocks superinfection by the same virus. PLoS Pathogens 13(3): e1006253
Halfmann R. (2016) A glass menagerie of low complexity sequences. Curr Opin Struct Biol. 38:9-16.
Close DW, Don Paul C, Langan PS, Wilce MC, Traore DA, Halfmann R, Rocha R, Waldo GS, Payne RJ, Rucker JB, and Prescott M. (2015) TGP, an extremely stable, non-aggregating fluorescent protein created by structure-guided surface engineering. Proteins: Structure, Function and Bioinformatics 83(7), 1225-1237.
Cai X, Chen J, Xu H, Liu S, Jiang Q, Halfmann R, and Chen ZJ. (2014) Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156(6), 1207-1222.
Holmes DL, Lancaster AK, Lindquist S, and Halfmann R. (2013) Heritable remodeling of yeast multicellularity by an environmentally responsive prion. Cell 153(1), 153-165.
Wang G, Wang X, Yu H, Wei S, Williams N, Holmes DL, Halfmann R, Naidoo J, Wang L, Li L, Chen S, Harran P, Lei X, Wang X. (2013) Small-molecule activation of the TRAIL receptor DR5 in human cancer cells. Nature Chemical Biology 9, 84–89.
Halfmann R*, Wright J*, Alberti S, Lindquist S, Rexach M. (2012). Prion formation by a yeast GLFG nucleoporin. Prion 6(4).
Halfmann R*, Jarosz DF*, Jones SK, Chang A, Lancaster AK, Lindquist S. (2012). Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482(7385), 363-8.
Halfmann R*, Alberti S*, Krishnan R, Lyle N, Pappu R, Lindquist S. (2011). Opposing effects of glutamine and asparagine govern prion formation by intrinsically disordered proteins. Molecular Cell 43(1), 72-84.
O'Donnell CW, Waldispühl J, Lis M, Halfmann R, Devadas S, Lindquist S, Berger B. (2011). A method for probing the mutational landscape of amyloid structure. Bioinformatics 27(13):i34-42
Alberti S*, Halfmann R*, King O, Kapila A, and Lindquist S. (2009). S. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137, 146-58.
Halfmann R and Lindquist S. (2008). Screening for Amyloid Aggregation by Semi-Denaturing Detergent-Agarose Gel Electrophoresis. Journal of Visualized Experiments 17.
Douglas P, Treusch S, Ren H, Halfmann R, Duennwald M, Lindquist S, and Cyr D. (2008). Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc. Natl. Acad. Sci. USA 105, 7206-7211.
(corresponding authorship; *equal authorship)
The Halfmann lab welcomes exceptionally motivated new or aspiring scientists to join us. Our research seeks to answer fundamental biological questions. We draw on biochemistry, cell, and systems biology to do so. Creative yet analytical, team-oriented individuals with a demonstrated affinity for quantitative approaches are especially encouraged to apply.