SV40 large tumor antigen
Simian virus 40 (virus)
It is well known that some viruses can change healthy cells into cancerous ones. Uncontrollable reproduction of such cells and the infection of new ones lead to the development of tumors, and very often to the death of the infected organism. One such virus is the simian virus 40, or SV40, which causes cancers in brain, bones and in the lymphatic system of monkeys and other animals. This virus encodes a deadly weapon, the Large Tumor Antigen (T antigen). This rather small protein, only 708 amino acids, takes part in the replication process of the viral DNA. It also participates in the transcription control and assembly of the virions. Therefore the discovery of its structure can help scientists to get a closer view at virus reproduction, and hopefully help to find ways to stop cancerous growth.
The structure of the protein can be divided into three domains with distinct functions. Twelve copies of the protein use their first domain to wrap around the DNA helix by forming two hexamer rings. The second domain contains a beta-hairpin structure that binds to a specific place in the DNA. The third domain is responsible for interactions with other proteins in the cellular environment. In the process of replication, an ATP molecule binds to the cleft between the first two domains. This induces conformational changes in the structure and the DNA strand is pulled for unwinding. Hydrolysis of ATP causes the beta-hairpins to move along the DNA helix, and after the release of ADP they finally bind to their new position on the chain. The complex is now ready for another round. Thus by using ATP hydrolysis as an energy source, the Large T-Antigen unwinds the viral DNA for copying. Although there is some controversy about whether SV40 causes cancer in humans or not, the structure of the Large T-Antigen is an excellent model for understanding the DNA replication process, a crucial step in the design of anti-cancer drugs.
Protein Data Bank (PDB)
Gai, D. Zhao, R. Li, D. Finkielstein, C.V. Chen, X.S.; "Mechanisms of conformational change for a replicative hexameric helicase of SV40 large tumor antigen."; Cell (Cambridge,Mass.); (2004) 119:47-60 PubMed:15454080.
author: Rossen Apostolov