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The complex crystal structure of the DNA binding domain of vIRF-1 from the oncogenic KSHV with DNAThe complex crystal structure of the DNA binding domain of vIRF-1 from the oncogenic KSHV with DNA
Structural highlights
FunctionVIRF1_HHV8P Plays a role in the inhibition of host innate response by repressing the expression of interferon-inducible genes and blocking host IRF1- and IRF3-mediated transcription. Blocks the interaction between host IRF3 and CREBBP. Regulates the host cellular metabolism by increasing glucose uptake, ATP production and lactate secretion through down-regulation of heterogeneous nuclear ribonuclear protein Q1/SYNCRIP. Mechanistically, induces ubiquitination and degradation of SYNCRIP through the ubiquitin-proteasome pathway by recruiting KLHL3/CUL3 ubiquitin ligase complex (PubMed:35538151). Disrupts host TP53 signaling pathway during viral infection by interacting with host USP7 and thereby decreasing the availability of USP7 for deubiquitinating and stabilizing TP53 (PubMed:26786098).[1] [2] [3] [4] [5] Publication Abstract from PubMedKaposi's sarcoma-associated herpesvirus encodes four viral homologues to cellular interferon regulatory factors (IRFs), where the most studied is vIRF-1. Even though vIRF-1 shows sequence homology to the N-terminal DNA-binding domain (DBD) of human IRFs, a specific role for this domain in vIRF-1's function has remained uncertain. To provide insights into the function of the vIRF-1 DBD, we have determined the crystal structure of it in complex with DNA and in its apo-form. Using a thermal stability shift assay (TSSA), we show that the vIRF-1 DBD binds DNA, whereas full-length vIRF-1 does not, suggesting a cis-acting regulatory mechanism in similarity to human IRFs. The complex structure of vIRF-1 DBD reveals interactions with the DNA backbone and the positioning of two arginines for specific recognition in the major grove. A superimposition with human IRF-3 reveals a similar positioning of the two specificity-determining arginines, and additional TSSAs indicate binding of vIRF-1 to an IRF-3 operator consensus sequence. The results from this study, therefore, provide support that vIRF-1 has evolved to bind DNA and plays a role in DNA binding in the context of transcriptional regulation and might act on some of the many operator sequences controlled by human IRF-3. The crystal structure of the DNA-binding domain of vIRF-1 from the oncogenic KSHV reveals a conserved fold for DNA binding and reinforces its role as a transcription factor.,Hew K, Dahlroth SL, Venkatachalam R, Nasertorabi F, Lim BT, Cornvik T, Nordlund P Nucleic Acids Res. 2013 Feb 21. PMID:23435230[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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