Abstract
ABSTRACTThe UL69 protein from human cytomegalovirus (HCMV) is a multifunctional regulatory protein and a member of the ICP27 protein family conserved throughout herpesviruses. UL69 plays many roles during productive infection, including the regulation of viral gene expression, nuclear export of intronless viral RNAs, and control of host cell cycle progression. Throughout the ICP27 protein family, an ability to self-associate is correlated with the functions of these proteins in transactivating certain viral genes. Here, we determined the domain boundaries of a globular ICP27 homology domain of UL69, which mediates self-association, and characterized the oligomeric state of the isolated domain. Size exclusion chromatography coupled with multiangle light scattering (SEC-MALS) revealed that residues 200 to 540 form a stable homo-tetramer, whereas a shorter region comprising residues 248 to 536 forms a homo-dimer. Structural analysis of the UL69 tetramer by transmission electron microscopy (TEM) revealed a dimer-of-dimers three-dimensional envelope with bridge features likely from a region of the protein unique to betaherpesviruses. The data provide a structural template for tetramerization and improve our understanding of the structural diversity and features necessary for self-association within UL69 and the ICP27 family.
Highlights
The UL69 protein from human cytomegalovirus (HCMV) is a multifunctional regulatory protein and a member of the ICP27 protein family conserved throughout herpesviruses
UL69 contains arginine-rich motifs which directly mediate RNA interactions, this interaction is not crucial for the nuclear export of transcripts, as mutants that do not bind RNA are still able to efficiently export unspliced viral mRNA [11]
UL69 self-association has been observed in yeast two-hybrid screens, and truncations suggested that the domain responsible was contained within residues 269 to 574, precisely the region that interacts with SPT6, suggestive of a correlation between self-association and this protein interaction [6]
Summary
The UL69 protein from human cytomegalovirus (HCMV) is a multifunctional regulatory protein and a member of the ICP27 protein family conserved throughout herpesviruses. UL69 forms numerous functionally important interactions with cellular proteins, allowing it to act posttranscriptionally to mediate the nuclear export and cytoplasmic accumulation of viral mRNAs and promote their translation. The oligomerization state of homologous herpesvirus proteins appears quite different; analytic gel filtration experiments suggested that the isolated KSHV open reading frame 57 (ORF57) IHD forms only homo-dimers [26].
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