Abstract
The replication of human polyomavirus JCV, which causes Progressive Multifocal Leukoencephalopathy, is initiated by the virally encoded T-antigen (T-ag). The structure of the JC virus T-ag origin-binding domain (OBD) was recently solved by X-ray crystallography. This structure revealed that the OBD contains a C-terminal pocket, and that residues from the multifunctional A1 and B2 motifs situated on a neighboring OBD molecule dock into the pocket. Related studies established that a mutation in a pocket residue (F258L) rendered JCV T-ag unable to support JCV DNA replication. To establish why this mutation inactivated JCV T-ag, we have solved the structure of the F258L JCV T-ag OBD mutant. Based on this structure, it is concluded that the structural consequences of the F258L mutation are limited to the pocket region. Further analyses, utilizing the available polyomavirus OBD structures, indicate that the F258 region is highly dynamic and that the relative positions of F258 are governed by DNA binding. The possible functional consequences of the DNA dependent rearrangements, including promotion of OBD cycling at the replication fork, are discussed.
Highlights
There are presently fourteen known human polyomavirus family members [1, 2]
A conserved feature of Polyomavirus T-antigens is a phenylalanine situated at the C-termini of their origin-binding domains (OBDs)
Using the T-antigen encoded by JC virus, we have investigated why this residue is critical for viral DNA replication
Summary
There are presently fourteen known human polyomavirus family members [1, 2]. Reasons for interest in these viruses include the diseases they are associated with, in immunocompromised individuals [3,4,5]. Polyomavirus T-ag's have been the focus of a number of recent structural studies (reviewed in [25, 26]) These structural studies have provided critical insights into the initiation process, such as establishing how the GAGGC pentanucleotides in the polyomavirus replication origins are recognized by the origin binding domains (OBD) within T-ag [27,28,29,30,31,32]. Additional experiments have revealed the multiple roles played by the T-ag helicase domains during origin melting [36,37,38], oligomerization [39, 40] and helicase activities ([39, 40]) Based on these studies, models depicting T-ag's multiple roles during the initiation of SV40 DNA replication have been proposed (e.g., [25, 26, 41])
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