Abstract
The fusion kinase DNAJ-PKAC is a recently identified driver of fibrolamellar hepatocellular carcinoma, an untreatable form of pediatric liver cancer. The fusion between the J-domain of DNAJ and the PKA catalytic subunit exhibits similar tertiary structure and unchanged in vitro catalytic activity providing little evidence of the mechanism of disease. Changes in conformational dynamics comparative to the wild-type kinase are likely leading to misregulation via altered interactions with substrate and regulatory protein. We have undertaken an exploration of the conformational landscape of the fusion protein over a wide range of biologically relevant timescales, discovering a link between histidine ionization, dynamics, and regulation
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