7NX5

Crystal structure of the Epstein-Barr Virus protein ZEBRA (BZLF1, Zta) bound to a methylated DNA duplex

Summary for 7NX5

• Entry DOI: 10.2210/pdb7nx5/pdb
• Descriptor: Trans-activator protein BZLF1, meZRE2 DNA (bottom strand), meZRE2 DNA (top strand), ... (4 entities in total)
• Functional Keywords: dna-binding protein, bzip transcription factor, viral protein
• Biological source: Epstein-Barr virus (strain B95-8) (HHV-4, Human herpesvirus 4); More
• Total number of polymer chains: 8
• Total formula weight: 53074.21

Authors

Bernaudat, F.,Petosa, C. (deposition date: 2021-03-17, release date: 2021-12-01, Last modification date: 2024-01-31)

Primary citation

Bernaudat, F.,Gustems, M.,Gunther, J.,Oliva, M.F.,Buschle, A.,Gobel, C.,Pagniez, P.,Lupo, J.,Signor, L.,Muller, C.W.,Morand, P.,Sattler, M.,Hammerschmidt, W.,Petosa, C.
Structural basis of DNA methylation-dependent site selectivity of the Epstein-Barr virus lytic switch protein ZEBRA/Zta/BZLF1.
Nucleic Acids Res., 50:490-511, 2022

PubMed Abstract: In infected cells, Epstein-Barr virus (EBV) alternates between latency and lytic replication. The viral bZIP transcription factor ZEBRA (Zta, BZLF1) regulates this cycle by binding to two classes of ZEBRA response elements (ZREs): CpG-free motifs resembling the consensus AP-1 site recognized by cellular bZIP proteins and CpG-containing motifs that are selectively bound by ZEBRA upon cytosine methylation. We report structural and mutational analysis of ZEBRA bound to a CpG-methylated ZRE (meZRE) from a viral lytic promoter. ZEBRA recognizes the CpG methylation marks through a ZEBRA-specific serine and a methylcytosine-arginine-guanine triad resembling that found in canonical methyl-CpG binding proteins. ZEBRA preferentially binds the meZRE over the AP-1 site but mutating the ZEBRA-specific serine to alanine inverts this selectivity and abrogates viral replication. Our findings elucidate a DNA methylation-dependent switch in ZEBRA's transactivation function that enables ZEBRA to bind AP-1 sites and promote viral latency early during infection and subsequently, under appropriate conditions, to trigger EBV lytic replication by binding meZREs.

PubMed: 34893887
DOI: 10.1093/nar/gkab1183

Experimental method

X-RAY DIFFRACTION (2.5 Å)