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

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

SUBMITTER: Tomasini MD 

PROVIDER: S-EPMC5768683 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature