The HECT2 family comprises 13 proteins organized into two subfamilies. The seven HECT domain-containing proteins are clustered into one subfamily, referred to as the "HECT" subfamily, while five RING ligases are grouped in the "KMT2-like" subfamily. A shared feature of these multi-domain E3 ligases is their enormous size, exceeding 2000 residues.
Within the HECT subfamily, further subdivisions are observed: HERC1 and HERC2 form one subset, whereas the other HECT proteins, HECTD4 and HUWE1, comprise another subgroup. Both HERC1 and HERC2 possess HERC subfamily-specific RCC1/RLD domains, and HERC2 additionally includes CYT5 (IPR001199), MIB (IPR010606), and Znf (IPR000433) domains. HECTD4 contains a SPRY domain (IPR001870), which likely coordinates protein-protein interactions. HUWE1 features ARM repeats and UBA (IPR041918) and WWE (IPR041918) domains.
The second subgroup includes UBR5, TRIPC, HECTD1, and CUL9 (an outlier in the RBR class). These proteins are relatively smaller and display multiple domains. HECTD1 contains Ankyrin repeats (IPR036770), SUN domain (IPR002110), and MIB (IPR010606) domains, while TRIPC includes both ARM and WWE domains. UBR5 is characterized by the E3 ubiquitin ligase EDD domain (IPR024725), along with RCC1/RLD, UBR box Zn-finger (IPR047503), and Poly(A)-binding protein C-terminal (PABC) domain (IPR002004). CUL9 (the outlier) contains a TRIAD domain at the C-terminal, and other domains such as DOC/APC10 and the Cullin Nedd8-2 domain (IPR001373) can act as scaffold proteins for other E3s by forming part of a multi-subunit ubiquitin complex.
The "KMT2-like" subfamily clusters together 5 RING E3 ligases, which display variable Zn-finger RING- and PHD-type domains. Like the HECT proteins, MYCB2 also possesses an RCC1/RLD domain, while other proteins contain PHR, Filamin/ABP280 repeats, DOC, and B-box type domains. KMT2C and KMT2D feature multiple PHD-type Zn-finger domains, an HMG box, and an FYRN motif at their C-terminal. UBR4 has an N-terminal UBR box domain (IPR045841), followed by Zn-finger and WD40 repeats, concluding with a C-terminal UBR domain. The protein RN213 contains an AAA5 domain (IPR003593) and Zn-finger RING-type and RZ-type (IPR046439) domains. This family's enormous size and variable domain architectures contribute to a poor MSA.
Members of the HECT2 family are enriched in biological processes related to the epigenetic regulation of gene expression, DNA metabolic processes, and branched polyubiquitination. They also mediate guanyl-nucleotide exchange, histone modifications, and protein ubiquitination. The PDB contains 53 structures covering 10 out of the 13 HECT2 E3s. HECT2 family members are likely to function as standalone proteins, supported by their considerable sequence lengths and multi-domain compositions, which align with their functional mode as independent proteins. Analysis of the ESI network for this family revealed 18 unique E3-specific substrates and one family-specific substrate. Currently, no small molecules explicitly target the HECT2 family.
For updated information and bibliography, please consult the supplementary information in Dutta et al. (2025, preprint)
The values represent E3 ligase confidence scores, calculated as the fraction of databases that annotate the protein as an E3 ligase (see preprint).
