A Structural Basis for BRD2/4-Mediated Host Chromatin Interaction and Oligomer Assembly of Kaposi Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus LANA Proteins.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Schulz, Thomas F
MetadataShow full item record
AbstractKaposi sarcoma-associated herpesvirus (KSHV) establishes a lifelong latent infection and causes several malignancies in humans. Murine herpesvirus 68 (MHV-68) is a related γ2-herpesvirus frequently used as a model to study the biology of γ-herpesviruses in vivo. The KSHV latency-associated nuclear antigen (kLANA) and the MHV68 mLANA (orf73) protein are required for latent viral replication and persistence. Latent episomal KSHV genomes and kLANA form nuclear microdomains, termed 'LANA speckles', which also contain cellular chromatin proteins, including BRD2 and BRD4, members of the BRD/BET family of chromatin modulators. We solved the X-ray crystal structure of the C-terminal DNA binding domains (CTD) of kLANA and MHV-68 mLANA. While these structures share the overall fold with the EBNA1 protein of Epstein-Barr virus, they differ substantially in their surface characteristics. Opposite to the DNA binding site, both kLANA and mLANA CTD contain a characteristic lysine-rich positively charged surface patch, which appears to be a unique feature of γ2-herpesviral LANA proteins. Importantly, kLANA and mLANA CTD dimers undergo higher order oligomerization. Using NMR spectroscopy we identified a specific binding site for the ET domains of BRD2/4 on kLANA. Functional studies employing multiple kLANA mutants indicate that the oligomerization of native kLANA CTD dimers, the characteristic basic patch and the ET binding site on the kLANA surface are required for the formation of kLANA 'nuclear speckles' and latent replication. Similarly, the basic patch on mLANA contributes to the establishment of MHV-68 latency in spleen cells in vivo. In summary, our data provide a structural basis for the formation of higher order LANA oligomers, which is required for nuclear speckle formation, latent replication and viral persistence.
CitationA Structural Basis for BRD2/4-Mediated Host Chromatin Interaction and Oligomer Assembly of Kaposi Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus LANA Proteins. 2013, 9 (10):e1003640 PLoS Pathog.
AffiliationDepartment of Structural Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
The following license files are associated with this item:
- Murine Gammaherpesvirus 68 Expressing Kaposi Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen (LANA) Reveals both Functional Conservation and Divergence in LANA Homologs.
- Authors: Gupta A, Oldenburg DG, Salinas E, White DW, Forrest JC
- Issue date: 2017 Oct 1
- The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA.
- Authors: Hellert J, Weidner-Glunde M, Krausze J, Lünsdorf H, Ritter C, Schulz TF, Lührs T
- Issue date: 2015 May 26
- KSHV but not MHV-68 LANA induces a strong bend upon binding to terminal repeat viral DNA.
- Authors: Ponnusamy R, Petoukhov MV, Correia B, Custodio TF, Juillard F, Tan M, Pires de Miranda M, Carrondo MA, Simas JP, Kaye KM, Svergun DI, McVey CE
- Issue date: 2015 Nov 16
- Cross-species conservation of episome maintenance provides a basis for in vivo investigation of Kaposi's sarcoma herpesvirus LANA.
- Authors: Habison AC, de Miranda MP, Beauchemin C, Tan M, Cerqueira SA, Correia B, Ponnusamy R, Usherwood EJ, McVey CE, Simas JP, Kaye KM
- Issue date: 2017 Sep
- Identification of Viral and Host Proteins That Interact with Murine Gammaherpesvirus 68 Latency-Associated Nuclear Antigen during Lytic Replication: a Role for Hsc70 in Viral Replication.
- Authors: Salinas E, Byrum SD, Moreland LE, Mackintosh SG, Tackett AJ, Forrest JC
- Issue date: 2016 Feb 1