HECT (Homologous to the E6-AP Carboxyl Terminus) proteins are a large group of E3 ubiquitin-ligases that play a role in the specificity and selectivity of ubiquitylation. The human genome encodes at least 20 different HECT domain proteins, which are grouped into two classes based on their E2 specificity. HECT enzymes also regulate the trafficking of many receptors, transporters, viral proteins and channels. Since HECT proteins are involved in the degradation of vital tumor suppressor molecules, it is theorized that some may contribute to tumorigenesis. HECTD2 (HECT domain-containing protein 2) is a 776 amino acid E3 ubiquitin-ligase that characteristically accepts ubiquitin from an E2 ubquitin-conjugating enzyme and directly transfers the ubiquitin to targeted substrates. Recently, HECTD2 haplotypes have been linked to the susceptibility of acquiring human prion diseases such as Creutzfeldt-Jakob Disease and kuru, which present after a long, clinically silent incubation period that seems to be determined by factors such as genetic background.