Epstein-Barr virus (EBV) is a clinically important human virus associated with several
cancers and is the etiologic agent of infectious mononucleosis. The viral nuclear
antigen-1 (EBNA1) is central to the replication and propagation of the viral genome and
likely contributes to tumourigenesis. We have compared EBNA1 homologues from
other primate lymphocryptoviruses (LCV) and found that the central glycine/alanine
repeat (GAr) domain, as well as predicted cellular protein (USP7 and CK2) binding
sites are present in homologues in the Old World primates, but not the marmoset;
suggesting that these motifs may have co-evolved. Using the resolved structure of the
C-terminal one third of EBNA1 (homodimerisation and DNA binding domain), we have
gone on to develop monomeric and dimeric models in silico of the full length protein.
The C-terminal domain is predicted to be structurally highly similar between
homologues, indicating conserved function. Zinc could be stably incorporated into the
model, bonding with two N-terminal cysteines predicted to facilitate multimerisation.
The GAr contains secondary structural elements in the models, while the protein
binding regions are unstructured, irrespective of the prediction approach used and
sequence origin. These intrinsically disordered regions may facilitate the diversity
observed in partner interactions. We hypothsise that the structured GAr could mask the
disordered regions, thereby protecting the protein from default degradation. In the
dimer conformation, the C-terminal tails of each monomer wrap around a proline-rich
protruding loop of the partner monomer, providing dimer stability, a feature which could
be exploited in therapeutic design
