Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis

Nature Communications
Ladan KhodaparastJoost Schymkowitz

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.

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Citations

Dec 22, 2019·Biomolecules·Chrysoula KokotidouAnd Anna Mitraki
Oct 22, 2019·FEMS Microbiology Reviews·Frederic D SchrammKristina Jonas
Jun 7, 2020·Nature Communications·Emiel MichielsJoost Schymkowitz
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May 4, 2021·Frontiers in Molecular Biosciences·Celien BollenJan Michiels
Jul 6, 2021·Frontiers in Molecular Biosciences·Michele MontiGian Gaetano Tartaglia
Jun 22, 2021·Frontiers in Molecular Biosciences·Laleh KhodaparastJoost Schymkowitz
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Nov 6, 2021·Journal of Peptide Science : an Official Publication of the European Peptide Society·Jay Kant Yadav
Dec 5, 2021·The FEBS Journal·Joëlle A J HousmansFrederic Rousseau

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Datasets Mentioned

BETA
PXD008685

Methods Mentioned

BETA
dynamic
transmission electron microscopy
atomic
infrared spectroscopy
flow cytometry
fluorescence microscopy
scanning electron microscopy
FACS
electrophoresis
fluorescence-activated cell sorting

Software Mentioned

Xcalibur
Proteome Discover
Scaffold
Prism
Intavis
Wyatt Dynamics
MASCOT
R
TANGO

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