A Structural Basis for BRD2/4-Mediated Host Chromatin Interaction and Oligomer Assembly of Kaposi Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus LANA Proteins.

2.50
Hdl Handle:
http://hdl.handle.net/10033/306167
Title:
A Structural Basis for BRD2/4-Mediated Host Chromatin Interaction and Oligomer Assembly of Kaposi Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus LANA Proteins.
Authors:
Hellert, Jan; Weidner-Glunde, Magdalena; Krausze, Joern; Richter, Ulrike; Adler, Heiko; Fedorov, Roman; Pietrek, Marcel; Rückert, Jessica; Ritter, Christiane; Schulz, Thomas F; Lührs, Thorsten
Abstract:
Kaposi 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.
Affiliation:
Department of Structural Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Citation:
A 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.
Journal:
PLoS pathogens
Issue Date:
Oct-2013
URI:
http://hdl.handle.net/10033/306167
DOI:
10.1371/journal.ppat.1003640
PubMed ID:
24146614
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the RG structure-based infectionbiology )SBIB)

Full metadata record

DC FieldValue Language
dc.contributor.authorHellert, Janen
dc.contributor.authorWeidner-Glunde, Magdalenaen
dc.contributor.authorKrausze, Joernen
dc.contributor.authorRichter, Ulrikeen
dc.contributor.authorAdler, Heikoen
dc.contributor.authorFedorov, Romanen
dc.contributor.authorPietrek, Marcelen
dc.contributor.authorRückert, Jessicaen
dc.contributor.authorRitter, Christianeen
dc.contributor.authorSchulz, Thomas Fen
dc.contributor.authorLührs, Thorstenen
dc.date.accessioned2013-12-03T13:03:08Z-
dc.date.available2013-12-03T13:03:08Z-
dc.date.issued2013-10-
dc.identifier.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.en
dc.identifier.issn1553-7374-
dc.identifier.pmid24146614-
dc.identifier.doi10.1371/journal.ppat.1003640-
dc.identifier.urihttp://hdl.handle.net/10033/306167-
dc.description.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.en
dc.language.isoenen
dc.rightsArchived with thanks to PLoS pathogensen
dc.titleA Structural Basis for BRD2/4-Mediated Host Chromatin Interaction and Oligomer Assembly of Kaposi Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus LANA Proteins.en
dc.typeArticleen
dc.contributor.departmentDepartment of Structural Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.en
dc.identifier.journalPLoS pathogensen

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