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Sci Rep. 2018 Jan 15;8(1):720. doi: 10.1038/s41598-017-18956-w.

Conformational Landscape of the PRKACA-DNAJB1 Chimeric Kinase, the Driver for Fibrolamellar Hepatocellular Carcinoma.

Author information

1
Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
2
Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.
3
Department of Biochemistry, Molecular Biology, and Biophysics. University of Minnesota, Minneapolis, MN, 55455, USA.
4
Schrödinger Inc., 120 West 45th Street, New York, NY, 10036, USA.
5
Theoretical Chemistry Institute, Jilin University, Changchun, Jilin Province, 130028, People's Republic of China.
6
Department of Pharmacology, University of California, San Diego, CA, 92093, USA.
7
Department of Chemistry and Biochemistry, University of California, San Diego, CA, 92093, USA.
8
Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA. simon@rockefeller.edu.

Abstract

In fibrolamellar hepatocellular carcinoma a single genetic deletion results in the fusion of the first exon of the heat shock protein 40, DNAJB1, which encodes the J domain, with exons 2-10 of the catalytic subunit of protein kinase A, PRKACA. This produces an enzymatically active chimeric protein J-PKAcα. We used molecular dynamics simulations and NMR to analyze the conformational landscape of native and chimeric kinase, and found an ensemble of conformations. These ranged from having the J-domain tucked under the large lobe of the kinase, similar to what was reported in the crystal structure, to others where the J-domain was dislodged from the core of the kinase and swinging free in solution. These simulated dislodged states were experimentally captured by NMR. Modeling of the different conformations revealed no obvious steric interactions of the J-domain with the rest of the RIIβ holoenzyme.

PMID:
29335433
PMCID:
PMC5768683
DOI:
10.1038/s41598-017-18956-w
[Indexed for MEDLINE]
Free PMC Article

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