Structure and Function of Human DnaJ Homologue Subfamily A Member 1 (DNAJA1) and Its Relationship to Pancreatic Cancer

Authors

Jaime L. Stark, University of Nebraska-LincolnFollow
Kamiya Mehla, University of Nebraska Medical CenterFollow
Nina V. Chaika, University of Nebraska Medical CenterFollow
Thomas B. Acton, The State University of New JerseyFollow
Rong Xiao, The State University of New Jersey
Pankaj K. Singh, University of Nebraska Medical Center
Gaetano T. Montelione, The State University of New JerseyFollow
Robert Powers, University of Nebraska-LincolnFollow

Date of this Version

2014

Citation

dx.doi.org/10.1021/bi401329a | Biochemistry 2014, 53, 1360−1372

Comments

© 2014 American Chemical Society

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.