A microbial sensor for discovering structural probes of protein misfolding and aggregation.
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, intracellular antibodies) that modulate the folding and solubility of virtually any protein-of-interest, including those associated with aggregation diseases (e.g., α-synuclein, amyloid-β protein). Taken together, these studies highlight the utility of engineered bacteria for rapidly and inexpensively uncovering potent anti-aggregation factors.
School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY USA.
Dujduan
D
Waraho-Zhmayev
Lizeta
L
Gkogka
Ta-Yi
TY
Yu
Matthew P
MP
DeLisa
D000682:Amyloid / Q000032:analysis* / Q000378:metabolism; D000906:Antibodies / Q000378:metabolism; D015374:Biosensing Techniques / Q000379:methods*; D001709:Biotechnology; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D057166:High-Throughput Screening Assays; D042541:Intracellular Space / Q000737:chemistry / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015336:Molecular Probe Techniques; D011485:Protein Binding; D017510:Protein Folding
D000682:Amyloid; D000906:Antibodies; D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins; C408585:twin-arginine translocase complex, E coli
aggregation; amyloid-β protein; antibody therapies; chemical chaperones; directed evolution; folding quality control; high-throughput screening; protein misfolding disorders; protein secretion; α-synuclein