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 large tumor antigen (also called the large T-antigen and abbreviated LTag or LT) is a
phosphorylated and in some strains is essential, although the molecular mechanism of its essentiality is unclear.[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. These truncated LTags retain their ability to interact with some cell cycle regulatory proteins and are involved in cell transformation but not in viral genome replication.[2][4]
J domain
The J domain is a
translated to the nucleus where it performs its replication-related functions.[3]
Origin-binding domain
The OBD binds the viral genome's
Nbs1. The OBD is required for viral replication.[3]
Zinc-binding domain
The zinc-binding and ATPase domains together comprise the
hexameric rings) is required for helicase activity, which begins at the origin of replication through coordination between the OBD, zinc-binding, and ATPase domains.[2][3]
ATPase domain
The zinc-binding and helicase domains of LTag shown bound to p53.[5]
The
topoisomerase 1 and the cell cycle regulator p53. LTag is unique among known AAA+ ATPases in that it is capable of initiating the melting of DNA around the origin; in most such cases a distinct initiator protein is responsible for this step, after which the helicase continues unwinding.[2][3]
Function
The major functions of LTag in the viral life cycle involve dysregulation of the host cell's
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]
LTag is encoded in the "early region" of the polyomavirus genome, so named because this region of the genome is expressed early in the infectious process. (The "late region" contains genes encoding the viral
N-terminal sequence of around 80 residues, while the remaining ~90 residues of STag are unshared.[4][7] In a few polyomaviruses - most notably murine polyomavirus, the first member of the family discovered and an efficient oncovirus - an additional protein called middle tumor antigen is expressed from the early region and is highly efficient at cellular transformation.[8]
Cellular transformation
Some, but not all, polyomaviruses are
neoplastic transformation in some cells. In oncogenic polyomaviruses, the tumor antigens are responsible for the transformation activity, although the exact molecular mechanisms vary from one virus to another.[3][2][9]
SV40
The
tumor suppressor protein p53; abrogating either binding site renders LTag unable to transform primary cultured cells.[10] In fact, p53 - now established as a key driver in carcinogenesis - was originally discovered by its ability to bind LTag.[10][11][12]
Murine polyomavirus
Murine polyomavirus (MPyV), described in the 1950s, was the first polyomavirus discovered and can cause tumors in rodents. 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.[10]
Merkel cell polyomavirus
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.[14][15]
Role in taxonomy
LTag is a large protein whose domains can be detected and annotated
phylogenetic studies suggesting that the evolutionary histories of LTag and major capsid protein VP1 are divergent and that some modern polyomavirus represent chimeric lineages.[17]
