Experimental and computational studies indicate specific binding of pVHL protein to Aurora-A kinase.
Overexpression of Aurora-A kinase is commonly detected in many cancers, whereas the von Hippel-Lindau protein (pVHL) is frequently mutated or absent in renal cell carcinoma and is involved in the Ub proteasome complex, an important degradation pathway. In order to establish a link between Aurora-A overexpression and lack of pVHL protein, we hypothesized that pVHL regulates Aurora-A expression through a physical interaction. We present the first evidence, from both biological assays and computational biology techniques, that human pVHL binds strongly to Aurora-A kinase. Extensive molecular modeling, docking, and dynamic simulations demonstrate that the structure of the pVHL protein would allow it to bind to the TPX2 binding region of Aurora-A. In view of Aurora-A's importance as a therapeutic target for the treatment of cancer, this observation provides novel insights into the Aurora-A/pVHL pathway. In addition, the detailed Aurora-A/pVHL binding structure obtained will be valuable for the design of future Aurora-A inhibitors as therapeutic agents.
Ferchichi
Imen
I
Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, Tunisia.
Stambouli
Nejla
N
Marrackchi
Raja
R
Arlot
Yannick
Y
Prigent
Claude
C
Fadiel
Ahmed
A
Odunsi
Kunle
K
Ben Ammar Elgaaied
Amel
A
Hamza
Adel
A
D000595:Amino Acid Sequence; D000818:Animals; D064127:Aurora Kinases; D019295:Computational Biology; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D055550:Protein Stability; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013816:Thermodynamics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases