4WB7

Crystal structure of a chimeric fusion of human DnaJ (Hsp40) and cAMP-dependent protein kinase A (catalytic alpha subunit)

Summary for 4WB7

• Entry DOI: 10.2210/pdb4wb7/pdb
• Related: 4WB5 4WB6 4WB8
• Descriptor: DnaJ homolog subfamily B member 1,cAMP-dependent protein kinase catalytic subunit alpha, PKI (5-24), ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: chaperone, catalysis, protein kinase, adenosine triphosphate, phosphorylation, chimera, fusion, fibrolamellar hepatocellular carinoma, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm. Isoform 2: Cell projection, cilium, flagellum : P17612
• Total number of polymer chains: 4
• Total formula weight: 101632.21

Authors

Cheung, J.,Ginter, C.,Cassidy, M.,Franklin, M.C.,Rudolph, M.J.,Hendrickson, W.A. (deposition date: 2014-09-02, release date: 2015-01-21, Last modification date: 2023-09-27)

Primary citation

Cheung, J.,Ginter, C.,Cassidy, M.,Franklin, M.C.,Rudolph, M.J.,Robine, N.,Darnell, R.B.,Hendrickson, W.A.
Structural insights into mis-regulation of protein kinase A in human tumors.
Proc.Natl.Acad.Sci.USA, 112:1374-1379, 2015

PubMed Abstract: The extensively studied cAMP-dependent protein kinase A (PKA) is involved in the regulation of critical cell processes, including metabolism, gene expression, and cell proliferation; consequentially, mis-regulation of PKA signaling is implicated in tumorigenesis. Recent genomic studies have identified recurrent mutations in the catalytic subunit of PKA in tumors associated with Cushing's syndrome, a kidney disorder leading to excessive cortisol production, and also in tumors associated with fibrolamellar hepatocellular carcinoma (FL-HCC), a rare liver cancer. Expression of a L205R point mutant and a DnaJ-PKA fusion protein were found to be linked to Cushing's syndrome and FL-HCC, respectively. Here we reveal contrasting mechanisms for increased PKA signaling at the molecular level through structural determination and biochemical characterization of the aberrant enzymes. In the Cushing's syndrome disorder, we find that the L205R mutation abolishes regulatory-subunit binding, leading to constitutive, cAMP-independent signaling. In FL-HCC, the DnaJ-PKA chimera remains under regulatory subunit control; however, its overexpression from the DnaJ promoter leads to enhanced cAMP-dependent signaling. Our findings provide a structural understanding of the two distinct disease mechanisms and they offer a basis for designing effective drugs for their treatment.

PubMed: 25605907
DOI: 10.1073/pnas.1424206112

Experimental method

X-RAY DIFFRACTION (1.9 Å)