UBE3A and the Ubiquitin Pathway
The UBE3A gene makes the UBE3A protein (also called E6-AP) and this protein is an important component of the ubiquitin-proteasome pathway (pictured below). This pathway is extremely important to all cells, especially brain neurons. The pathway enables a small protein molecule, ubiquitin, to be attached to certain proteins, thereby causing them to be degraded [1]. Ubiquitin is a small protein (76 amino acids in length) that can be tagged onto other proteins in order to initiate their destruction. As pictured, E1 and E2 proteins activate (yellow) and transfer ubiquitin to E3. There are many different types of E3 proteins and UBE3A is one of them. UBE3A is able to chemically attach ubiquitin onto target proteins (red). Important in UBE3A's protein structure is the HECT domain, a molecular pocket that enables ubiquitin and the target protein to come into close proximity, allowing for attachment of the activated ubiquitin molecule [2]. Some protein targets for UBE3A are known but it is currently unknown which protein targets are linked to the precise brain dysfunction in AS. UBE3A is closely associated with neuronal synaptic function.
1. Scheffner M, Nuber U and Huibregtse JM. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature, 1995. 373(6509): p. 81-3.
2. Verdecia MA, Joazeiro CA, Wells NJ, et al. Conformational flexibility underlies ubiquitin ligation mediated by the WWP1 HECT domain E3 ligase. Mol Cell, 2003. 11(1): p. 249-59.