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

Olivieri, Cristina; Walker, Caitlin; Karamafrooz, Adak; Wang, Yingjie; Manu, V. S.; Porcelli, Fernando; Blumenthal, Donald K.; Thomas, David D.; Bernlohr, David A.; Simon, Sanford M.; Taylor, Susan S.; Veglia, Gianluigi

doi:10.1038/s42003-021-01819-6

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

Journal Article · Wed Mar 10 00:00:00 EST 2021 · Communications Biology

DOI:https://doi.org/10.1038/s42003-021-01819-6· OSTI ID:1817013

^[1]; ^[1]; Karamafrooz, Adak ^[1]; Wang, Yingjie ^[1]; Manu, V. S. ^[1]; ^[2]; ^[3]; ^[1]; ^[1]; Simon, Sanford M. ^[4]; ^[5]; ^[1]

Univ. of Minnesota, Minneapolis, MN (United States)
University of Tuscia, Viterbo (Italy)
Univ. of Utah, Salt Lake City, UT (United States)
Rockefeller Univ., New York, NY (United States)
Univ. of California San Diego, La Jolla, CA (United States)

An aberrant fusion of the DNAJB1 and PRKACA genes generates a chimeric protein kinase (PKA-C^DNAJB1) 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-C^DNAJB1 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-C^DNAJB1 alters specific recognitions and interactions between substrates and regulatory partners contributing to dysregulation.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Utah, Salt Lake City, UT (United States)

Sponsoring Organization:: American Heart Association (AHA); National Institutes of Health (NIH); USDOE

OSTI ID:: 1817013

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 4; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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