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NMR Mapping of the Allosteric Network in the Oncogenic Protein Kinase A Chimera Dnajb1‐PRKACA
Author(s) -
Karamafrooz Adak N,
Li Geoffrey N,
Simon Sanford M,
Taylor Susan S,
Veglia Gianluigi N
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb92
Subject(s) - allosteric regulation , biology , protein kinase a , microbiology and biotechnology , p110α , biochemistry , kinase , signal transduction , enzyme , protein kinase b
Protein Kinase A (PKA) is a well‐known member of the serine‐threonine protein kinase superfamily. PKA signaling is involved in the control of a wide variety of cellular processes from metabolism to ion channel activation, cell growth and differentiation, gene expression and apoptosis. Recent genomic studies have identified a chimeric fusion of the catalytic subunit of cAMP‐dependent Protein Kinase A (PKA) with the DNAJB1 chaperone on the N‐terminus (DNAJB1‐PRKACA) as a single driver for the progression of Fibrolamellar Hepatocellular Carcinoma (FL‐HCC). Previous X‐ray studies show a compact structure of the chimeric kinase, with the DNAJB1 moiety tucked onto the core of the enzyme. In contrast, our NMR studies show that the enzyme's core and the DNAJB1 appendix move independently and that these conformational dynamics affect the binding of the endogenous inhibitor peptide PKI. Additionally, the conformational dynamics of DNAJB1 also affect the allosteric cooperativity of the enzyme, which is a central property for substrate affinity and catalysis. These structural and dynamic dysfunctions may be correlated to the aberrant cellular function of this kinase and progression of FL‐HCC. Support or Funding Information NIH