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Biochemistry Department - Primary Faculty

Amy Ruschak, Ph.D.

Assistant Professor

Education

  • Ph.D.: Yale University, Department of Chemistry, 2008
    Postdoc: University of Toronto, Departments of Molecular Genetics, Biochemistry, and Chemistry, 2012

Research Interests

Inflammasomes are multicomponent protein complexes that form in response to injury or pathogen invasion and activate signaling pathways that give rise to inflammation as part of the innate immune response. Activation of inflammasomes is deregulated in numerous disease states including autoinflammatory diseases such as hereditary fevers, metabolic disorders such as type II diabetes and atherosclerosis, as well as certain cancers. Many of these disease states benefit from treatments that target the inflammasome or other proteins that are directly activated by it.

Inflammasome assembly is initiated by oligomerization of scaffolding proteins when pathogen or danger-associated stimuli are detected in the cytosol of eukaryotic cells. Such oligomers recruit and activate a protease, caspase-1, which then initiates signaling pathways that result in inflammation by cleaving a number of substrates, including the pro-inflammatory cytokines interleukin-1β and interleukin-18. An atomic level description of the mechanism by which the inflammasome activates and regulates the proteolytic activity of caspase-1 is being determined by characterizing in vitro assembled complexes using an entourage of biophysical techniques. This includes cutting edge NMR methods to characterize the structure and dynamics of caspase-1; fluorescence techniques to characterize its enzymatic activity; and calorimetry to measure the energetics of the interactions of caspase-1 with other proteins in the inflammasome. A mechanistic description of inflammasome function is important not only for elucidating how this complex functions as a central hub in immune response, but it is also a necessary prerequisite for developing novel and rationale approaches for therapeutic intervention.

Selected References

  • Velyvis A., Ruschak A. M., and Kay L. E.
    “An economical method for production of (2)H, (13)CH3-threonine for solution NMR studies of large protein complexes: application to the 670 kDa proteasome”
    PLoS One 7 (9): e43725 (2012). Read article in PubMedCentral
  • Ruschak A. M. and Kay L. E.
    “Proteasome allostery as a population shift between interchanging conformers”
    Proc Natl Acad Sci U S A 109 (50): E3454-62 (2012). Read article in PubMedCentral
  • Ruschak A. M., Slassi M., Kay L. E., and Schimmer A. D.
    “Novel proteasome inhibitors to overcome bortezomib resistance”
    J Natl Cancer Inst 103 (13): 1007-17 (2011).
  • Religa T. L., Ruschak A. M., Rosenzweig R., and Kay L. E.
    “Site-directed methyl group labeling as an NMR probe of structure and dynamics in supramolecular protein systems: applications to the proteasome and to the ClpP protease”
    J Am Chem Soc 133 (23): 9063-8 (2011).
  • Ruschak A. M., Velyvis A., and Kay L. E.
    “A simple strategy for (1)(3)C, (1)H labeling at the Ile-gamma2 methyl position in highly deuterated proteins”
    J Biomol NMR 48 (3): 129-35 (2010).
  • Ruschak A. M., Religa T. L., Breuer S., Witt S., and Kay L. E.
    “The proteasome antechamber maintains substrates in an unfolded state”
    Nature 467 (7317): 868-71 (2010).
  • Ruschak A. M. and Kay L. E.
    “Methyl groups as probes of supra-molecular structure, dynamics and function”
    J Biomol NMR 46 (1): 75-87 (2010).
  • Ruschak A. M. and Miranker A. D.
    “The role of prefibrillar structures in the assembly of a peptide amyloid”
    J Mol Biol 393 (1): 214-26 (2009).
  • Ruschak A. M. and Miranker A. D.
    “Fiber-dependent amyloid formation as catalysis of an existing reaction pathway”
    Proc Natl Acad Sci U S A 104 (30): 12341-6 (2007). Read article in PubMedCentral
  • Ruschak A. M., Mathews D. H., Bibillo A., Spinelli S. L., Childs J. L., Eickbush T. H., and Turner D. H.
    “Secondary structure models of the 3' untranslated regions of diverse R2 RNAs”
    RNA 10 (6): 978-87 (2004). Read article in PubMedCentral
  • Glazier S., Barron J. A., Morales N., Ruschak A. M., Houston P. L., and Abruña H. D.
    “Quenching Dynamics of the Photoluminescence of [Ru(bpy)3]2+-Pendant PAMAM Dendrimers by Nitro Aromatics and Other Materials”
    Macromolecules 36 (4): 1272-8 (2003).
Faculty's publications at pubmed