Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A
Year: 2021
Type: article
Abstract: An 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.
Source: Communications Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,290
Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, American Heart Association, University of Utah, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: Protein Oxidation, Structure, & Function in Aging Muscle, G1342145945, G1716646000, Site-Directed Modification of Muscle Protein Structural Dynamics, G1880192570, Structural and functional role of protein kinase A in the development of cardiac myxomas, Console Upgrade for a 600 MHz NMR Spectrometer, G2751668057, G2775129233, G3809222662, G4902419486, G4911192384, G5228957411, G5446755904, Center for therapeutic targeting of the Fusion Oncoprotein of Fibrolamellar Hepatocellular Carcinoma, G7323793941, G7677835708, Mapping Allosteric Cooperativity in Protein Kinases, G9000269273, Mayo Clinic Hepatobiliary SPORE, Protein structural biophysics driving drug discovery for cardiac calcium transport regulation, producing translational advances and mechanistic insights, Lessons Learned from PKA: Assembly of Dynamic Macromolecular Switches
OpenAlex ID: W3134740672