Allosteric activation of a bacterial stress sensor

Area of Science:

• Microbiology
• Molecular Biology
• Cellular Biology

Background:

• Gram-negative bacteria possess an outer membrane that is crucial for their survival.
• Envelope stress, often caused by unfolded outer membrane proteins (OMP), activates cellular defense mechanisms.
• The periplasmic protease DegS plays a key role in initiating cellular pathways to resolve envelope stress.

Purpose of the Study:

• To elucidate the mechanism by which the DegS protease is regulated in response to unfolded OMPs.
• To identify the specific molecular interactions that lead to the activation of DegS.

Main Methods:

• Investigated the allosteric regulation of the DegS protease.
• Focused on the role of the PDZ domain of DegS in protein-protein interactions.
• Utilized biochemical assays to study the binding of unfolded OMP C-terminal sequences to DegS.

Main Results:

• Demonstrated that inhibition of DegS is relieved through an allosteric mechanism.
• Showed that the C-terminal sequences of unfolded OMPs directly bind to the PDZ domain of DegS.
• Confirmed that this binding event is critical for activating the envelope stress response pathway.

Conclusions:

• The binding of unfolded OMP C-terminal sequences to the DegS PDZ domain is a key regulatory step in the Gram-negative bacterial envelope stress response.
• This allosteric regulation allows DegS to sense and respond to the presence of misfolded outer membrane proteins.
• Understanding this mechanism provides insights into bacterial cell envelope homeostasis and potential therapeutic targets.