1. Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis
- Author
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Ladan Khodaparast, Emiel Michiels, Johan Van Eldere, Filip Claes, Matyas Desager, Laleh Khodaparast, Mohammad Shahrooei, Rodrigo Gallardo, Hannah Wilkinson, Per Hammarström, Wubishet Tadesse, Frederic Rousseau, Nikolaos N. Louros, K. Peter R. Nilsson, Meine Ramakers, Sebastien Carpentier, Joost Schymkowitz, Lydia M. Young, Abram Aertsen, and Reshmi Ramakrishnan
- Subjects
0301 basic medicine ,Acinetobacter baumannii ,Protein Folding ,Infectious Medicine ,animal structures ,Proteome ,Science ,General Physics and Astronomy ,Infektionsmedicin ,Protein aggregation ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Protein Aggregates ,0302 clinical medicine ,Antibiotic resistance ,Bacterial Proteins ,medicine ,Escherichia coli ,lcsh:Science ,Multidisciplinary ,biology ,Chemistry ,General Chemistry ,biology.organism_classification ,3. Good health ,Cell biology ,030104 developmental biology ,Proteostasis ,Protein folding ,lcsh:Q ,030217 neurology & neurosurgery ,Bacteria - Abstract
Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy., Aggregation is sequence-specific and nucleated by short aggregating protein segments (APR). Here authors use a multidisciplinary approach to show that in E.coli some frequently occurring APRs lead to protein aggregation and ultimately bacterial cell death, which could serve as antibacterial strategy.
- Published
- 2018