Neurotoxic protein oligomers

Oligomers and fibrils (amyloids) formed from several proteins are associated with a variety of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, and ALS. Unfortunately, for many of the proteins involved in these diseases, the mechanisms responsible for amyloid formation and the structures of various intermediates (e.g. oligomers and protofibrils) along the fibrillization pathway are notoriously difficult to study. This is especially true of oligomeric species, which are difficult to isolate, metastable, and disproportionately toxic relative to higher molecular weight protofibrils and fibrils. The continued study of oligomeric species will require breakthroughs in structural biology as well as an improved understanding of protein homeostasis and fibrilization kinetics. We are developing tools that will aid in the isolation of neurotoxic protein oligomers with the ultimate goal of establishing structure-function relationships for these species.

 

Metabolically-controlled redox catalysis

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Metabolic engineering benefits from the tunable and tightly controlled reactions afforded by biological systems. The reaction space available to specific organisms can be expanded through directed evolution or the insertion of heterologous pathways, but is still relatively limited compared to synthetic chemistry. In an effort to expand the scope of biological catalysis, we are exploring extracellular electron transfer as a means to achieve metabolic control over exogenous transition-metal catalyzed reactions. As an example, we used the electroactive bacterium Shewanella oneidensis to control a metal-catalyzed radical polymerization. We found that polymerization activity was strongly coupled to bacterial metabolism and the expression of specific electron transport proteins. Metabolic control over polymerization opens avenues for applying synthetic biology and cellular engineering techniques to produce polymers and materials with emergent properties. Along with these efforts, we are using our knowledge of synthetic biology, inorganic chemistry, and chemical engineering to expand metabolically-controlled redox catalysis to alternative electroactive bacteria and synthetic reactions.

BIOLOGICALLY-PRODUCED METAL NANOPARTICLES

Metal nanoparticles produced from bacterial reduction of soluble metal salts show promise as catalysts for processes relevant to water treatment, environmental remediation, and medicine. In some cases, nanoparticles produced in this manner exhibit superior activity to those synthesized using more traditional methods. However, control over nanoparticle size and crystal morphology is still a challenge and varies significantly between organisms. Well-defined genotype-phenotype linkages must be established to realize microbial production of designer materials. Towards this goal, we employ the electroactive metabolism of Shewanella oneidensis and the stress-response pathways of Deinococcus radiodurans to better understand the biochemical mechanisms of nanoparticle formation. We use tools in synthetic biology, material characterization, and analytical chemistry to elucidate these relationships and rationally engineer materials with improved catalytic activity.

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