McsB forms a gated kinase chamber to mark aberrant bacterial proteins for degradation
Bence Hajdusits1, Marcin J Suskiewicz1, Nikolas Hundt2
1Research Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, Austria.
Abstract:
In Gram-positive bacteria, the McsB protein arginine kinase is central to protein quality control, labeling aberrant molecules for degradation by the ClpCP protease. Despite its importance for stress response and pathogenicity, it is still elusive how the bacterial degradation labeling is regulated. Here, we delineate the mechanism how McsB targets aberrant proteins during stress conditions. Structural data reveal a self-compartmentalized kinase, in which the active sites are sequestered in a molecular cage. The 'closed' octamer interconverts with other oligomers in a phosphorylation-dependent manner and, unlike these 'open' forms, preferentially labels unfolded proteins. In vivo data show that heat-shock triggers accumulation of higher order oligomers, of which the octameric McsB is essential for surviving stress situations. The interconversion of open and closed oligomers represents a distinct regulatory mechanism of a degradation labeler, allowing the McsB kinase to adapt its potentially dangerous enzyme function to the needs of the bacterial cell.
Insights
The McsB protein arginine kinase regulates bacterial protein degradation during stress. Its structure changes, allowing it to target unfolded proteins and survive heat shock, crucial for bacterial cell health.
Area of Science:
- Microbiology and Molecular Biology
- Bacterial Protein Quality Control Mechanisms
Background:
- McsB protein arginine kinase is vital for protein quality control in Gram-positive bacteria.
- It labels aberrant proteins for degradation by the ClpCP protease, impacting stress response and pathogenicity.
- The precise regulatory mechanism of McsB-mediated degradation labeling remains largely unknown.
Purpose of the Study:
- To elucidate the regulatory mechanism by which McsB targets aberrant proteins under stress conditions.
- To investigate the structural basis for McsB's substrate specificity and oligomerization.
- To understand the role of McsB oligomerization in bacterial stress survival.
Main Methods:
- X-ray crystallography to determine the structure of McsB and its oligomeric states.
- In vitro kinase assays to assess McsB activity and substrate preference.
- In vivo studies using heat shock models in Gram-positive bacteria to observe McsB behavior.
Main Results:
- Structural data revealed McsB as a self-compartmentalized kinase with active sites sequestered in a 'closed' octameric form.
- The 'closed' octamer preferentially labels unfolded proteins and interconverts with 'open' oligomers in a phosphorylation-dependent manner.
- In vivo, heat shock induces higher-order McsB oligomers, with the octameric form being essential for stress survival.
Conclusions:
- The interconversion between open and closed McsB oligomers is a novel regulatory mechanism for degradation labeling.
- This dynamic regulation allows McsB to control its enzymatic activity, adapting to cellular needs during stress.
- The octameric McsB plays a critical role in bacterial adaptation and survival under stress conditions.
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