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Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

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Abstract

Epstein–Barr virus 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 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 (homodimerization 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 hypothesize 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.

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Acknowledgments

M.H. is a recipient of a Higher Education Commission of Pakistan and Dow University of Health Sciences Scholarship.

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  1. Mushtaq Hussain

    Present address: Institute of Biological, Biochemical and Pharmaceutical Sciences, Dow University of Health Sciences, Karachi, Pakistan

  2. Derek Gatherer

    Present address: Division of Biomedical and Life Sciences, Lancaster University, Lancaster, LA1 4YG, UK

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  1. College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK

    Mushtaq Hussain, Derek Gatherer & Joanna B. Wilson

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Hussain, M., Gatherer, D. & Wilson, J.B. Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1. Virus Genes 49, 358–372 (2014). https://doi.org/10.1007/s11262-014-1101-9

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