UBE3A Protein Property Prediction

Though it has been known for some time that Angleman Syndrome is caused by the lack of a functional maternal copy of UBE3A, the biochemical causes for the disease symptoms are still poorly understood.

The INTERPRO prediction package identified the HECT domain as the sole domain of this protein, suggesting a role as a ubiquitin-protein ligase. It also classified UBE3A as an IMP dehydrogenase/GMP reductase family protein.

Searching for localization signals, PSORT suggested a primarily extracellular role for UBE3A, giving the total distribution as follows:
52%: extracellular, including cell wall
12%: cytoplasmic
12%: nuclear
12%: endoplasmic reticulum
8%: vesicles of secretory system
4%: mitochondrial

According to the Human Protein Resource Database, the primary localization of this protein is in the cytoplasm, though it also occurs in the nucleus, so PSORT at least was close to the right track for this one.

The COILS program predicted a significant probability of a coiled-coil structure in the region of amino acid residues 150 and 200, as the graphical output below shows.

TMpred suggested the possibility of anywhere from one to three trans-membrane domains in the protein, though interestingly the PSORT prediction does not suggest that UBE3A is membrane-bound. The Human Protein Reference Database similarly does not suggest a membrane-bound role for UBE3A, though it does reference numerous protein-protein interactions of UBE3A in the ubiquitin pathway. Since many protein-protein interactions rely upon hydrophobic interactions, it could be that hydrophobic stretches of UBE3A are giving a false positive score for transmembrane domains.

Expasy predicted the molecular weight to be just over 100kD and the pI to be 5.12.

In 1999, the crystal structure of UBE3A was reported. With the crystal structural data, the need for structural prediction software is greatly reduced for this protein, though it is interesting to analyze the predictions against the actual structure. From both the reported data and the visibly apparent structure, this protein shows no transmembrane domains, contrary to the prediction given by TMpred. With the structural data available, the next step in better understanding the protein is to model its various interactions with different ligands and proteins to understand the ubiquitin protein degradation pathway more fully, and in particular its relationship to Angelman Syndrome.