Jason Yi Submitted:

UBE3A was originally discovered as E6-associated protein (E6AP) in the context of cancer caused by the human papilloma virus (HPV). During HPV infection, the virus expresses the E6 oncoprotein, which binds to UBE3A and hijacks its ubiquitin ligase activity. These observations have long suggested that the E6-binding domain (E6BD) is central to UBE3A function. However, if and whether this region is critical to endogenous UBE3A activity remains unknown. Here, we used functional variant analyses and found the E6BD is an allosteric regulator of UBE3A activity. These data implicate a convergent mechanism of UBE3A regulation across various disorders.