ArticleThe Journal of biological chemistry2008
Analysis of conformational changes during activation of protein kinase Pak2 by amide hydrogen/deuterium exchange.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 37 citations in OpenAlex.
- Role of activated p21-activated kinase 2 in methylmercury-induced embryotoxic effects on mouse blastocysts.Toxicology research · 2023Article
- Article
- Role of caspase-3-cleaved/activated PAK2 in brusatol-triggered apoptosis of human lung cancer A549 cells.Toxicology research · 2022Article
- Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases.Molecular cell · 2020Article
- PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions.Scientific reports · 2019Article
- STE20/PAKA Protein Kinase Gene Releases an Autoinhibitory Domain through Pre-mRNA Alternative Splicing in the DermatophyteInternational journal of molecular sciences · 2018Article
- Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach.Human genomics · 2013Article
- Article
- Amide hydrogen/deuterium exchange & MALDI-TOF mass spectrometry analysis of Pak2 activation.Journal of visualized experiments : JoVE · 2011Article
- Phosphorylation of caspase-7 by p21-activated protein kinase (PAK) 2 inhibits chemotherapeutic drug-induced apoptosis of breast cancer cell lines.The Journal of biological chemistry · 2011Article
- Methods for the Analysis of High Precision Differential Hydrogen Deuterium Exchange Data.International journal of mass spectrometry · 2011Article
- Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis.PloS one · 2010Article
- Localizing the membrane binding region of Group VIA Ca2+-independent phospholipase A2 using peptide amide hydrogen/deuterium exchange mass spectrometry.The Journal of biological chemistry · 2009Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
During apoptotic stress, protein kinase Pak2 is cleaved by caspase 3 to form a heterotetramer that is constitutively activated following autophosphorylation. The active protein kinase migrates slightly slower than the inactive holoenzyme when analyzed by gel filtration, suggesting an expanded conformation. Activation of Pak2 comprises a series of structural changes resulting from caspase cleavage, ATP binding, and autophosphorylation of Pak2. Changes at each step were individually analyzed by amide hydrogen/deuterium exchange coupled with mass spectrometry and compared with inactive Pak2. The auto-inhibited form was shown to bind ATP in the active site, with minor changes in the glycine loop and the autoinhibitory domain (AID). Caspase cleavage produced significant changes in solvent accessibility in the AID and upper lobe of the catalytic domain. Cleavage of ATP-bound Pak2 relaxes the allosteric inhibition, as shown by increased solvent accessibility in the upper and lower lobes, including the G-helix, facilitating the autophosphorylation of two sites required for activation, Ser-141 in the regulatory domain and Thr-402 in the catalytic domain. Autophosphorylation increased the amide hydrogen/deuterium exchange solvent accessibility of the contact region between the AID and the G-helix, the E-F loop, and the N terminus. Thus, activation of Pak2 via caspase cleavage is associated with structural relaxation of Pak2 that allows for complete auto-phosphorylation, resulting in a more comprehensive solvent-exposed and conformationally dynamic enzyme.
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