Large T antigen
Domain
The J domain is essential for multiple viral activities, including virion assembly, viral DNA replication, transformation and transcriptional activation.
The LXCXE motif specifically binds to host pRB, RBL1, and RBL2.
The origin-binding domain (T-ag OBD) interacts specifically with several pentameric sequences 5'-GAGGC-3' in the SV40 origin of DNA replication.
The zinc finger region contributes to protein-protein interactions essential for the assembly of stable T-antigen hexamers at the origin of replication. The hexamers are required for subsequent alterations in the structure of origin DNA (PubMed:1851875, PubMed:2173794).
The C-terminal region is involved in interaction with host FAM111A. It is also required for the host range and adenovirus helper functions of the virus (PubMed:23093934).
The ATP binding/ATPase domain is required for proper hexamer assembly and helicase activity.
Cdc4 phospho-degron (CPD) region is involved in interaction with host FBW7gamma isoform.
Function
Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Has processive 3'-5' DNA helicase activity which requires a short 3' single-stranded region and ATP; other (d)NTPs can partially replace ATP (PubMed:2826443, PubMed:2826446). Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription. May inactivate the growth-suppressing properties of the E3 ubiquitin ligase CUL7.
Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.
Unwinds G4 DNA (planar arrays of 4 guanine bases stabilized by hydrogen bonds, parallel and antiparallel arrays were tested); unwinding occurs in the 3'-5' direction, requires a 3' single-stranded end and hydrolyzable ATP (PubMed:9016557).
Post-translational modifications
Phosphorylated on both serine and threonine residues. Phosphorylation on Ser-120 and Ser-123 inhibits viral replication, while phosphorylation on Thr-124 enhances replication by activating the DNA-binding domain. Phosphorylation on Thr-701 is required for binding to host FBW7gamma isoform. Dephosphorylated preferentially by PP2A on Ser-120, Ser-123, Ser-677 and perhaps Ser-679. Small t antigen inhibits the dephosphorylation by the AC form of PP2A.
O-Glycosylated near the C-terminal region.
Acetylated by CBP in a TP53-dependent manner.
Cellular localization
- Host nucleus
Alternative names
Large T antigen, LT, LT-AG, DNA 3'-5' helicase large T antigen