4uzb
KSHV LANA (ORF73) C-terminal domain mutant bound to LBS1 DNA (R1039Q, R1040Q, K1055E, K1109A, D1110A, A1121E, K1138S, K1140D, K1141D)
Structural highlights
FunctionLANA1_HHV8P Multifunctional protein that plays a role in the replication and long-term persistence of the viral episomal genome in dividing cells. Binds to mitotic chromosomes via its N-terminal region and to a 16-bp imperfect palindrome within the origin of replication (oriP) located in the viral terminal repeat (TR) through its C-terminal. Tethers viral episomes to chromosomes during mitosis. Plays a critical role in the shutdown of lytic gene expression during the early stage of infection by interacting with host TRIM28. Plays also a role in the repression of host NF-kappa-B activity upon TNF-alpha stimulation by promoting the proteasomal degradation of host RELA (PubMed:21697472). Promotes nuclear localization and cleavage of host STAT6 leading to constitutive activation of the IL13/STAT6 signaling pathway to promote viral latency (PubMed:28099521). Interacts with and modulates the histone methyltransferase MLL1 complex activity, leading to its recruitment on viral DNA terminal repeats changing the dynamic of histone H3 methylated 'Lys-4'(H3K4me) profile during the initial hours following infection (PubMed:34850113).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedKaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 A resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related gamma-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 A resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains ("LANA speckles"), a hallmark of KSHV latency. The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA.,Hellert J, Weidner-Glunde M, Krausze J, Lunsdorf H, Ritter C, Schulz TF, Luhrs T Proc Natl Acad Sci U S A. 2015 May 6. pii: 201421804. PMID:25947153[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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