A microbial sensor for discovering structural probes of protein misfolding and aggregation
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Author list: Waraho-Zhmayev D., Gkogka L., Yu T.-Y., Delisa M.P.
Publisher: Taylor and Francis Group
Publication year: 2013
Journal: Prion (1933-6896)
Volume number: 7
Issue number: 2
Start page: 151
End page: 156
Number of pages: 6
ISSN: 1933-6896
eISSN: 1933-690X
Languages: English-Great Britain (EN-GB)
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Abstract
In all cell types, protein homeostasis, or 'proteostasis,' is maintained by sophisticated quality control networks that regulate protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation. In one notable example, Escherichia coli employ a proteostasis system that determines whether substrates of the twin-arginine translocation (Tat) pathway are correctly folded and thus suitable for transport across the tightly sealed cytoplasmic membrane. Herein, we review growing evidence that the Tat translocase itself discriminates folded proteins from those that are misfolded and/or aggregated, preferentially exporting only the former. Genetic suppressors that inactivate this mechanism have recently been isolated and provide direct evidence for the participation of the Tat translocase in structural proofreading of its protein substrates. We also discuss how this discriminatory 'folding sensor' has been exploited for the discovery of structural probes (e.g., sequence mutations, pharmacologic chaperones and intracellular antibodies) that modulate the folding and solubility of virtually any protein-of-interest, including those associated with aggregation diseases (e.g., a-synuclein and amyloid-฿ protein). Taken together, these studies highlight the utility of engineered bacteria for rapidly and inexpensively uncovering potent anti-aggregation factors. ฉ 2013 Landes Bioscience. ฉ 2013 Landes Bioscience.
Keywords
Amyloid-ß protein, Antibody therapies, Chemical chaperones, Directed evolution, Folding quality control, High-throughput screening, Protein misfolding disorders, Protein secretion, α-synuclein
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