4fgn | pdb_00004fgn
Crystal structure of the SV40 large T-antigen origin bining domain bound to Site I DNA
Structural highlights
FunctionLT_SV40 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. 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.[1] [2] [3] [4] [5] [6] [7] Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.[8] [9] [10] [11] [12] [13] [14] Publication Abstract from PubMedPolyomavirus origins of replication contain multiple G(A/G)GGC sequences; the high affinity binding element for the viral initiator T-antigen (T-ag). The Site I regulatory region of Simian Virus 40, involved in the repression of transcription and the enhancement of DNA replication initiation, contains two GAGGC sequences arranged head-to-tail and separated by a 7 bp AT-rich sequence. We have solved a 3.2 A co-structure of the SV40 origin-binding domain (OBD) bound to Site I. We have also established that T-ag assembly on Site I is limited to the formation of a single hexamer. These observations have enabled an analyses of the role(s) of the OBDs bound to the Site I pentanucleotides in hexamer formation. Of interest, they reveal a correlation between the OBDs bound to Site I and a pair of OBD subunits in the previously described hexameric spiral structure. Based on these findings, we propose that spiral assembly is promoted by pentanucleotide pairs arranged in a head to tail manner. Finally, the possibility that "spiral-assembly " by OBD subunits may account for the heterogeneous distribution of pentanucleotides found in the origins of replication of polyomaviruses is discussed. ANALYSIS OF THE CO-STRUCTURE OF THE SV40 T-ANTIGEN ORIGIN BINDING DOMAIN WITH SITE I REVEALS A CORRELATION BETWEEN GAGGC SPACING AND SPIRAL ASSEMBLY.,Meinke G, Phelan PJ, Harrison C, Bullock PA J Virol. 2012 Dec 26. PMID:23269808[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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