A microbial sensor for discovering structural probes of protein misfolding and aggregation

作者：Waraho Zhmayev Dujduan; Gkogka Lizeta; Yu Ta Yi; DeLisa Matthew P^*

来源：Prion, 2013, 7(2): 151-156.

DOI：10.1073/pnas.1210140109

• aggregation
• alpha-synuclein
• amyloid-beta protein
• antibody therapies
• chemical chaperones
• directed evolution
• folding quality control
• high-throughput screening
• protein misfolding disorders
• protein secretion

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., alpha-synuclein and amyloid-beta protein). Taken together, these studies highlight the utility of engineered bacteria for rapidly and inexpensively uncovering potent anti-aggregation factors.

• 出版日期2013-4