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A Conserved Structural Role for the Walker-A Lysine in P-Loop Containing Kinases.
Fatlum Hajredini1,2, Ranajeet Ghose1,2,3,4
1Department of Chemistry and Biochemistry, The City College of New York, New York, NY, United States.
Frontiers in Molecular Biosciences
|October 18, 2021
Summary
A conserved lysine in bacterial kinases stabilizes an inactive state, preventing ATP binding. This regulatory mechanism is shared between bacterial tyrosine kinases and shikimate kinases, suggesting a widespread control strategy.
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Bacterial tyrosine kinases (BY-kinases) and shikimate kinases (SKs) are structurally distinct enzyme families.
- Both families possess similar catalytic site geometries, including Walker-A, Walker-B, and DxD motifs.
- Previous work showed a lysine in BY-kinases' Walker-A motif induces an inactive conformation.
Purpose of the Study:
- To investigate the role of the Walker-A lysine in shikimate kinases (SKs).
- To determine if the structural role of the Walker-A lysine is conserved between BY-kinases and SKs.
- To explore the implications for enzyme regulation in P-loop containing kinases.
Main Methods:
- Enhanced sampling molecular dynamics simulations.
- Analysis of conserved structural interactions within kinase catalytic sites.
- Comparative analysis across different SK members, including those with and without canonical Walker-B motifs.
Main Results:
- Similar to BY-kinases, the Walker-A lysine in SKs mediates interactions that stabilize an inactive state.
- This inactive state deviates from the optimal Mg2+•ATP coordination required for catalysis.
- This lysine-mediated structural role is conserved in SKs, irrespective of their Walker-B motif variations.
Conclusions:
- The structural role of the Walker-A lysine in stabilizing an inactive state is conserved between SKs and BY-kinases.
- This suggests a widely conserved regulatory mechanism in P-loop containing enzymes.
- The findings highlight a fundamental aspect of enzyme regulation in ancient kinase families.
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