Large tumor antigen

Some polyomavirus LTag proteins - most notably the well-studied SV40 large tumor antigen from the SV40 virus - are oncoproteins that can induce neoplastic transformation in the host cell.

[3] In some polyomaviruses, truncated variants of the LTag protein are produced through alternative splicing that do not include the helicase (zinc-binding and ATPase) components.

[2][4] The J domain is a DnaJ molecular chaperone that is required for viral genome replication in vivo (but is dispensable in cell-free laboratory experiments).

This unstructured linker region also contains a nuclear localization sequence, which triggers the host cell to transport the protein from the cytoplasm where is it translated to the nucleus where it performs its replication-related functions.

Formation of dodecamer structures (two hexameric rings) is required for helicase activity, which begins at the origin of replication through coordination between the OBD, zinc-binding, and ATPase domains.

The early region typically contains at least two genes and is transcribed as a single messenger RNA processed by alternative splicing.

In oncogenic polyomaviruses, the tumor antigens are responsible for the transformation activity, although the exact molecular mechanisms vary from one virus to another.

MPyV has three early proteins; in addition to LTag and STag it also expresses middle tumor antigen, which is primarily responsible for the virus's transforming activity.

Comparison of the sequences of MCPyV and SV40 LTag predicts that they have similar capacities for protein-protein interactions, including preservation of the Rb and p53 binding sites.

[9] Mutations in MCPyV LTag associated with tumors consist of large C-terminal truncations that eliminate the DNA replication functions of the protein by removing the zinc-binding and ATPase/helicase domains, without affecting these protein-protein interaction sites.

[16] This system has been questioned by phylogenetic studies suggesting that the evolutionary histories of LTag and major capsid protein VP1 are divergent and that some modern polyomavirus represent chimeric lineages.

The zinc -binding and ATPase / helicase domains of the large tumor antigen in hexameric form, shown with bound ADP (white), zinc (black spheres), and double-stranded DNA (center, light and dark gray). [ 1 ]
The zinc-binding and helicase domains of LTag shown bound to p53 . [ 5 ]
Genome structure of WU virus , a typical human polyomavirus. The early genes are at left, comprising LTag (purple) and STag (blue); the late genes are at right, and the origin of replication is shown at the top of the figure. [ 6 ]