Biology Reference
In-Depth Information
2. It transactivates transcription from viral early and late promoters.
3. It inactivates the cellular Rb repressor, which activates E2F responsive promot-
ers to move the cell cycle from the G
o
/G
1
to the G
1
/S interface.
4. It prevents expression of cellular cytokines and chemokines expression with
antiviral properties.
5. It controls both the G
1
/S and G
2
/
Μ
transition points in the cell cycle.
The regions of the viral protein involved in these functions were broadly
mapped, and consequently more than one function was usually affected by the
mutation. A core region was identified between amino acid residues 450 and 552
in which mutations in this region affected all identified functions of the IE86
protein. Site-specific mutations in this region demonstrated that the functions of
the IE86 protein can be separated and more clearly defined. There are other
functional domains and conserved regions within the IE86 protein that need to be
defined. The crystal structure of the IE86 protein should be demonstrated to
better understand the functional domains. The tertiary structure of the IE86
protein appears critical for function. For example, the histidine residues at 446
and 452 are critical and possibly associated with a double zinc finger domain that
determines a three-dimensional structure for the interaction with a variety of
cellular and viral proteins. Mutation of the histidine residues at 446 and 452
affects all IE86 protein functions in the context of the viral genome. The proline
and tyrosine residues 535 and 537, respectively, which are a part of a conserved
five-amino acid stretch in the core domain, affect transcription of early viral
promoters. The acidic amino acids between residues 550 and 573 affect early
viral promoter activation. The conserved glutamine residue 548 affects control of
cell cycle progression. These critical amino acids of the IE86 protein are potential
targets for new and unique antivirals. Since the current antivirals for the treatment
of HCMV infection are of limited efficacy with high frequencies of adverse
effects, it is important to understand the tertiary structure of the carboxyl domain
of the IE86 protein to develop new treatments for HCMV infection.
Acknowledgements
We thank members of the Stinski lab and Jeffery Meier for critical review
of this manuscript. Our work was supported by grant AI-13562 from the National Institutes of
Health.
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