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

Hussain, M., Gatherer, D. and Wilson, J. B. (2014) Modelling the structure of full-length Epstein-Barr virus nuclear antigen 1. Virus Genes, 49(3), pp. 358-372. (doi:10.1007/s11262-014-1101-9)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wilson, Professor Joanna and Gatherer, Dr Derek
Authors: Hussain, M., Gatherer, D., and Wilson, J. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Virus Genes
Publisher:Springer
ISSN:0920-8569
ISSN (Online):1572-994X
Copyright Holders:Copyright © 2014 Springer
First Published:First published in BMC Veterinary Research 11:10
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH