title: Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer.
abstract: Pancreatic cancer has a dismal 5 year survival rate of 5.5% that has not been improved over the past 25 years despite an enormous amount of effort. Thus, there is an urgent need to identify truly novel yet druggable protein targets for drug discovery. The human protein DnaJ homologue subfamily A member 1 (DNAJA1) was previously shown to be downregulated 5-fold in pancreatic cancer cells and has been targeted as a biomarker for pancreatic cancer, but little is known about the specific biological function for DNAJA1 or the other members of the DnaJ family encoded in the human genome. Our results suggest the overexpression of DNAJA1 suppresses the stress response capabilities of the oncogenic transcription factor, c-Jun, and results in the diminution of cell survival. DNAJA1 likely activates a DnaK protein by forming a complex that suppresses the JNK pathway, the hyperphosphorylation of c-Jun, and the anti-apoptosis state found in pancreatic cancer cells. A high-quality nuclear magnetic resonance solution structure of the J-domain of DNAJA1 combined with a bioinformatics analysis and a ligand affinity screen identifies a potential DnaK binding site, which is also predicted to overlap with an inhibitory binding site, suggesting DNAJA1 activity is highly regulated.
authors: Department of Chemistry, University of Nebraska-Lincoln , Lincoln, Nebraska 68588, United States.
authors: Jaime L
authors: JL
authors: Stark
authors: Kamiya
authors: K
authors: Mehla
authors: Nina
authors: N
authors: Chaika
authors: Thomas B
authors: TB
authors: Acton
authors: Rong
authors: R
authors: Xiao
authors: Pankaj K
authors: PK
authors: Singh
authors: Gaetano T
authors: GT
authors: Montelione
authors: Robert
authors: R
authors: Powers
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000473:pathology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D008024:Ligands