Biology Reference
In-Depth Information
Deletion analysis has revealed that the HDAC-binding site in MCMV IE1 is
between amino acid residues 100 and 310. A peptide comprised of these amino
acids retains HDAC-binding capability and the potential to augment transcription
from the MIEP. A deletion in a similar helical region of HCMV IE1 also eliminates
the augmenting effect (Stenberg et al. 1990) and abolishes IE1-mediated dispersal
of ND10 (Ishov et al. 1997; Lee et al. 2004). More detailed deletion analysis
revealed that removing amino acid sequences surrounding the HDAC binding
domain eliminates the ability of IE1 to disperse ND10 (Q. Tang and G. Maul,
unpublished data). Structurally, this suggests that IE1 possesses a bipartite ND10-
binding domain that differs from the HDAC-binding domain. A bipartite p107-bind-
ing domain has also been reported for HCMV IE1 (Poma et al. 1996).
HCMV IE1 and MCMV IE1 share only 12% amino acid homology, mostly in
the highly acidic C-terminal region. Moreover, HCMV IE1 is 20% shorter than
MCMV IE1. Therefore these two proteins appear to have very little in common.
However, they share the same genetic structure, as well as the ability to disperse
ND10 and augment viral transcription. We need additional comparative and func-
tional analyses, particularly if the mouse system is to be used as an experimental
small animal model. Although the primary structures of HCMV IE1 and MCMV
IE1 differ significantly, their secondary structures are surprisingly similar. One
unresolved aspect of the apparent structural similarity between HCMV IE1 and
MCMV IE1 is the position of the small ubiquitin modifier (SUMO). In HCMV IE1,
SUMO is at aa 450 (Xu et al. 2001), and in MCMV IE1 we find the SUMO con-
sensus sequence at aa 223. These rather large covalent modifications could have a
strong differential influence on the 3D structure of IE1, and thus could influence
the functional properties of the two different IE1s. Since SUMO modifies very
small amounts of protein at any given time (Johnson 2004), these SUMO subsets
may have additional functions. In HCMV IE1, deletion of the SUMO modification
site reduces the levels of IE2 transcript and their translation products (Nevels et al.
2004a) and PML desumoylation (Lee et al. 2004). In MCMV IE1, the putative
SUMO modification site is within the HDAC binding site (G. Maul, unpublished
observations); its precise functions, however, remain unknown.
Though IE1 is not essential for productive infection, it appears to be very impor-
tant for replicative success. Isolating the respective functions of this molecule and
assigning them to its different interfaces may provide a rational basis for the search
for small interfering molecules. Such molecules may induce an IE1 minus pheno-
type, substantially lowering productive infection.
IE1 Counteracts the Host Cell's Silencing Mechanisms
The major immediate early transcript is differentially spliced to produce a number
of proteins. The two major and best-investigated proteins, IE1 and IE2, have in
common exons 2 and 3 but differ in the larger exon 4 (IE1) and exon 5 (HCMV IE2
and its MCMV homolog, IE3). These proteins act synergistically to activate early
