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Title: | Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A | Authors: | Olivieri, Cristina Walker, Caitlin Karamafrooz, Adak Wang, Yingjie Manu, V S Porcelli, Fernando Blumenthal, Donald K Thomas, David D Bernlohr, David A Sandford, Simon M Taylor, Susan S Veglia, Gianluigi |
Journal: | COMMUNICATIONS BIOLOGY | Issue Date: | 2021 | 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. |
URI: | http://hdl.handle.net/2067/43279 | ISSN: | 2399-3642 | DOI: | 10.1038/s42003-021-01819-6 | Rights: | Attribution-NoDerivs 3.0 United States |
Appears in Collections: | A1. Articolo in rivista |
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