[SCAN] Structural characterization of LANA: Impact on Herpesvirus Latency

Scan Seminar

Title: Structural characterization of LANA: Impact on Herpesvirus Latency

Speaker: Colin E. McVey, DPhil

From: Structural Genomics Lab, ITQB

Abstract:

Herpesviruses establish life-long latent infections cell in which they remain dormant in the cell under the radar of our immune system. During latency, gammaherpesviruses, such as Kaposi's sarcoma-associated herpesvirus (KSHV), persist as multicopy, circularized genomes in the cell nucleus and express a small subset of viral genes. KSHV latency-associated nuclear antigen (LANA) is the predominant gene expressed during latent infection. C-terminal LANA binds KSHV terminal repeat (TR) DNA to mediate DNA replication. TR DNA binding also allows tethering of the viral genome to mitotic chromosomes to mediate DNA segregation to daughter nuclei.
We describe here the crystal structure of the murine gammaherpesvirus 68 LANA DNA binding domain, which is homologous to that of KSHV LANA. The structure revealed a dimer and we identified residues involved in the interaction with viral DNA. Mutation of these residues abolished DNA binding and viable latency establishment in a mouse model of infection. We also show that there are two faces to LANA and have identified a positively charged patch on the dimer surface opposite to the DNA binding region and found this patch exerts an important role in the virus's ability to expand latent infection in vivo. This work elucidates the structure of the LANA DNA binding domain and identifies a novel surface feature that is critical for viral latent infection, likely by acting through a host cell protein.
Future perspectives will focus on ways to target potential sites on LANA and disrupt LANA’s ability to maintain latency and viral DNA replication and thus abolish herpesvirus persistence in the cell. This has huge implications for herpesvirus related cancer treatment and prevention.