Insights into the initiation of JC virus DNA replication derived from the crystal structure of the T-antigen origin binding domain.

Gretchen Meinke,Peter A Bullock,Paul J Phelan,Jong Shin,Jacques Archambault,Radha Kalekar,Andrew Bohm,Michael J Imperiale

doi:10.1371/journal.ppat.1003966

Gretchen Meinke, Peter A Bullock + Show 6 more

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https://doi.org/10.1371/journal.ppat.1003966

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Abstract

JC virus is a member of the Polyomavirus family of DNA tumor viruses and the causative agent of progressive multifocal leukoencephalopathy (PML). PML is a disease that occurs primarily in people who are immunocompromised and is usually fatal. As with other Polyomavirus family members, the replication of JC virus (JCV) DNA is dependent upon the virally encoded protein T-antigen. To further our understanding of JCV replication, we have determined the crystal structure of the origin-binding domain (OBD) of JCV T-antigen. This structure provides the first molecular understanding of JCV T-ag replication functions; for example, it suggests how the JCV T-ag OBD site-specifically binds to the major groove of GAGGC sequences in the origin. Furthermore, these studies suggest how the JCV OBDs interact during subsequent oligomerization events. We also report that the OBD contains a novel “pocket”; which sequesters the A1 & B2 loops of neighboring molecules. Mutagenesis of a residue in the pocket associated with the JCV T-ag OBD interfered with viral replication. Finally, we report that relative to the SV40 OBD, the surface of the JCV OBD contains one hemisphere that is highly conserved and one that is highly variable.

Highlights

There are twelve known human polyomavirus members (e.g., [1,2]) and for immuno-compromised individuals, there is an increasing association between these viruses and human diseases
We propose a molecular model for the oligomerization of the JC virus (JCV) T-antigen origin-binding domain (OBD) that is based upon the crystal structure
We report a novel pocket that modeling studies suggest is available when the OBD is site- bound to DNA and may represent a possible starting point for structure-based drug design

Summary

Introduction

There are twelve known human polyomavirus members (e.g., [1,2]) and for immuno-compromised individuals, there is an increasing association between these viruses and human diseases (reviewed in [3,4,5]). JC virus (JCV) is the causative agent of Progressive Multifocal Leukoencephalopathy ((PML); reviewed in [6,7,8]); a demyelinating disease of the central nervous system [9,10]. Further interest in JCV, which is present in approximately 50% of the general population [13], stems from the fact that a promising new treatment of multiple sclerosis (the monoclonal antibody Tysabri) is known to be associated with the induction of PML (reviewed in [8,14,15]). Studies have suggested a possible association between infection with JCV and human brain and non-central nervous system tumors [16,17].

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