Activation of Protein Kinase Pak2: A Molecular Mechanism

During apoptotic stress, a series of structural changes in protein kinase Pak2 leads to its activation. These changes result from caspase cleavage, ATP binding, and autophosphorylation of Pak2. The exact mechanism of activation was investigated by researchers at the University of California, who found that caspase cleavage produces significant changes in solvent accessibility in the autoinhibitory domain and upper lobe of the catalytic domain. This structural relaxation allows for complete autophosphorylation, resulting in a more solvent-exposed and conformationally dynamic enzyme.

Key Takeaways:

• Caspase cleavage of Pak2 is a key step in its activation, producing significant changes in solvent accessibility in the autoinhibitory domain and upper lobe of the catalytic domain.
• The active protein kinase migrates slightly slower than the inactive holoenzyme when analyzed by gel filtration, suggesting an expanded conformation.
• Autophosphorylation of Pak2 requires the relaxation of allosteric inhibition, which is achieved through caspase cleavage.
• The activation of Pak2 is associated with structural changes in the autoinhibitory domain, glycine loop, and upper lobe of the catalytic domain.
• The researchers used amide hydrogen/deuterium exchange coupled with mass spectrometry to analyze the changes in solvent accessibility at each step of Pak2 activation.
• The activated Pak2 kinase has increased solvent accessibility in the contact region between the autoinhibitory domain and the G-helix, the E-F loop, and the N terminus.
• The study provides insights into the molecular mechanism of Pak2 activation, which may have implications for the development of new therapies targeting this enzyme.

Statistics:

• 52nd volume of the Journal of Biological Chemistry, page 36397-36405, contains the study by Hsu and colleagues.
• 2008 was the publication year of the Journal of Biological Chemistry study.
• 283 was the volume number of the Journal of Biological Chemistry, in which the study was published.
• Riverside, CA 92521, is the contact address of J.A. Traugh, University of California, Dept. of Biochemistry.
• Bethesda, MD 20814-3996, is the publisher contact information for the Journal of Biological Chemistry.

Sources:

• Hsu, Y.H. et al. (2008). Analysis of Conformational Changes during Activation of Protein Kinase Pak2 by Amide Hydrogen/Deuterium Exchange. Journal of Biological Chemistry, 283(52), 36397-36405.
• University of California, Dept. of Biochemistry, Riverside, CA 92521, USA.
• American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA.