A computational analysis of substrate binding strength by phosphorylase kinase and protein kinase A

2002 ◽  
Vol 15 (2) ◽  
pp. 104-111 ◽  
Author(s):  
Ross I. Brinkworth ◽  
James Horne ◽  
Bostjan Kobe
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Computational Analysis ◽  
Substrate Binding ◽  
Phosphorylase Kinase ◽  
Binding Strength ◽  
Kinase A

scholarly journals Water-mediated conformational preselection mechanism in substrate binding cooperativity to protein kinase A

2018 ◽  
Vol 115 (15) ◽  
pp. 3852-3857 ◽  
Author(s):  
Piotr Setny ◽  
Marta D. Wiśniewska
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Binding Sites ◽  
Substrate Binding ◽  
Binding Region ◽  
Allosteric Coupling ◽  
Single Water Molecule ◽  
Allosteric Pathway ◽  
Significant Attention ◽  
Kinase A

Substrate binding cooperativity in protein kinase A (PKA) seems to involve allosteric coupling between the two binding sites. It received significant attention, but its molecular basis still remains not entirely clear. Based on long molecular dynamics of PKA and its complexes, we characterized an allosteric pathway that links ATP binding to the redistribution of states adopted by a protein substrate positioning segment in favor of those that warrant correct binding. We demonstrate that the cooperativity mechanism critically depends on the presence of water in two distinct, buried hydration sites. One holds just a single water molecule, which acts as a switchable hydrogen bond bridge along the allosteric pathway. The second, filled with partially disordered solvent, is essential for providing a smooth free energy landscape underlying conformational transitions of the peptide binding region. Our findings remain in agreement with experimental data, also concerning the cooperativity abolishing effect of the Y204A mutation, and indicate a plausible molecular mechanism contributing to experimentally observed binding cooperativity of the two substrates.

scholarly journals Author Correction: Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Cristina Olivieri ◽  
Caitlin Walker ◽  
Adak Karamafrooz ◽  
Yingjie Wang ◽  
V. S. Manu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Substrate Binding ◽  
Kinase A

A Correction to this paper has been published: https://doi.org/10.1038/s42003-021-02006-3

scholarly journals Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Cristina Olivieri ◽  
Caitlin Walker ◽  
Adak Karamafrooz ◽  
Yingjie Wang ◽  
V. S. Manu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Molecular Mechanisms ◽  
Substrate Binding ◽  
Chimeric Protein ◽  
Α Subunit ◽  
Primary Driver ◽  
Chimeric Construct ◽  
J Domain ◽  
Kinase A

AbstractAn aberrant fusion of the DNAJB1 and PRKACA genes generates a chimeric protein kinase (PKA-CDNAJB1) in which the J-domain of the heat shock protein 40 is fused to the catalytic α subunit of cAMP-dependent protein kinase A (PKA-C). Deceivingly, this chimeric construct appears to be fully functional, as it phosphorylates canonical substrates, forms holoenzymes, responds to cAMP activation, and recognizes the endogenous inhibitor PKI. Nonetheless, PKA-CDNAJB1 has been recognized as the primary driver of fibrolamellar hepatocellular carcinoma and is implicated in other neoplasms for which the molecular mechanisms remain elusive. Here we determined the chimera’s allosteric response to nucleotide and pseudo-substrate binding. We found that the fusion of the dynamic J-domain to PKA-C disrupts the internal allosteric network, causing dramatic attenuation of the nucleotide/PKI binding cooperativity. Our findings suggest that the reduced allosteric cooperativity exhibited by PKA-CDNAJB1 alters specific recognitions and interactions between substrates and regulatory partners contributing to dysregulation.

Regulation of spontaneous and induced resumption of meiosis in mouse oocytes by different intracellular pathways

Reproduction ◽  
2000 ◽  
pp. 377-383 ◽  
Author(s):  
L Leonardsen ◽  
A Wiersma ◽  
M Baltsen ◽  
AG Byskov ◽  
CY Andersen
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Mitogen Activated Protein Kinase ◽  
Meiotic Maturation ◽  
Mouse Oocytes ◽  
Mitogen Activated Protein ◽  
Dependent Signal ◽  
Kinase Pathway ◽  
Kinase A

The mitogen-activated protein kinase-dependent and the cAMP-protein kinase A-dependent signal transduction pathways were studied in cultured mouse oocytes during induced and spontaneous meiotic maturation. The role of the mitogen-activated protein kinase pathway was assessed using PD98059, which specifically inhibits mitogen-activated protein kinase 1 and 2 (that is, MEK1 and MEK2), which activates mitogen-activated protein kinase. The cAMP-dependent protein kinase was studied by treating oocytes with the protein kinase A inhibitor rp-cAMP. Inhibition of the mitogen-activated protein kinase pathway by PD98059 (25 micromol l(-1)) selectively inhibited the stimulatory effect on meiotic maturation by FSH and meiosis-activating sterol (that is, 4,4-dimethyl-5alpha-cholest-8,14, 24-triene-3beta-ol) in the presence of 4 mmol hypoxanthine l(-1), whereas spontaneous maturation in the absence of hypoxanthine was unaffected. This finding indicates that different signal transduction mechanisms are involved in induced and spontaneous maturation. The protein kinase A inhibitor rp-cAMP induced meiotic maturation in the presence of 4 mmol hypoxanthine l(-1), an effect that was additive to the maturation-promoting effect of FSH and meiosis-activating sterol, indicating that induced maturation also uses the cAMP-protein kinase A-dependent signal transduction pathway. In conclusion, induced and spontaneous maturation of mouse oocytes appear to use different signal transduction pathways.

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