Proteopedia

4uzc

KSHV LANA (ORF73) C-terminal domain, spiral: hexagonal crystal formKSHV LANA (ORF73) C-terminal domain, spiral: hexagonal crystal form

Structural highlights

4uzc is a 4 chain structure with sequence from Human gammaherpesvirus 8. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.7Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LANA1_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 PubMed

Kaposi 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

  1. ↑ Ballestas ME, Chatis PA, Kaye KM. Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science. 1999 Apr 23;284(5414):641-4. PMID:10213686 doi:10.1126/science.284.5414.641
  2. ↑ Viejo-Borbolla A, Ottinger M, Brüning E, Bürger A, König R, Kati E, Sheldon JA, Schulz TF. Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's Sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J Virol. 2005 Nov;79(21):13618-29. PMID:16227282 doi:10.1128/JVI.79.21.13618-13629.2005
  3. ↑ Barbera AJ, Chodaparambil JV, Kelley-Clarke B, Joukov V, Walter JC, Luger K, Kaye KM. The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science. 2006 Feb 10;311(5762):856-61. PMID:16469929 doi:311/5762/856
  4. ↑ Li X, Liang D, Lin X, Robertson ES, Lan K. Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen reduces interleukin-8 expression in endothelial cells and impairs neutrophil chemotaxis by degrading nuclear p65. J Virol. 2011 Sep;85(17):8606-15. PMID:21697472 doi:10.1128/JVI.00733-11
  5. ↑ Sun R, Liang D, Gao Y, Lan K. Kaposi's sarcoma-associated herpesvirus-encoded LANA interacts with host KAP1 to facilitate establishment of viral latency. J Virol. 2014 Jul;88(13):7331-44. PMID:24741090 doi:10.1128/JVI.00596-14
  6. ↑ Gjyshi O, Roy A, Dutta S, Veettil MV, Dutta D, Chandran B. Activated Nrf2 Interacts with Kaposi's Sarcoma-Associated Herpesvirus Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene Repression. J Virol. 2015 Aug;89(15):7874-92. PMID:25995248 doi:10.1128/JVI.00895-15
  7. ↑ Sun Z, Jha HC, Robertson ES. Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis. J Virol. 2015 Oct;89(20):10206-18. PMID:26223641 doi:10.1128/JVI.01524-15
  8. ↑ Gupta N, Thakker S, Verma SC. KSHV encoded LANA recruits Nucleosome Assembly Protein NAP1L1 for regulating viral DNA replication and transcription. Sci Rep. 2016 Sep 7;6:32633. PMID:27599637 doi:10.1038/srep32633
  9. ↑ Wang C, Zhu C, Wei F, Gao S, Zhang L, Li Y, Feng Y, Tong Y, Xu J, Wang B, Yuan Z, Robertson ES, Cai Q. Nuclear Localization and Cleavage of STAT6 Is Induced by Kaposi's Sarcoma-Associated Herpesvirus for Viral Latency. PLoS Pathog. 2017 Jan 18;13(1):e1006124. PMID:28099521 doi:10.1371/journal.ppat.1006124
  10. ↑ Chiu YF, Sugden AU, Fox K, Hayes M, Sugden B. Kaposi's sarcoma-associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally. J Cell Biol. 2017 Sep 4;216(9):2745-2758. PMID:28696226 doi:10.1083/jcb.201702013
  11. ↑ Tan M, Li S, Juillard F, Chitas R, Custodio TF, Xue H, Szymula A, Sun Q, Liu B, Alvarez AL, Chen S, Huang J, Simas JP, McVey CE, Kaye KM. MLL1 is regulated by KSHV LANA and is important for virus latency. Nucleic Acids Res. 2021 Nov 29. pii: 6438035. doi: 10.1093/nar/gkab1094. PMID:34850113 doi:http://dx.doi.org/10.1093/nar/gkab1094
  12. ↑ Hellert J, Weidner-Glunde M, Krausze J, Lunsdorf H, Ritter C, Schulz TF, Luhrs T. The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA. Proc Natl Acad Sci U S A. 2015 May 6. pii: 201421804. PMID:25947153 doi:http://dx.doi.org/10.1073/pnas.1421804112

4uzc, resolution 3.70Å

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