The RING8 family comprises 18 proteins predominantly classified as TRIM E3 ligases. These proteins contain either RING-type or B-box-type Zn-fingers as their catalytic domains. Within this family, two distinct subfamilies have been identified based on their domain architecture and sequence similarity.
The first subfamily (TRIM+SPRY) encompasses approximately half of the proteins and is characterized by three specific domains: the SPRY domain, the COS domain, and the Fibronectin type III domain (IPR003961). The Fibronectin type III domain is a structural module featuring Arg-Gly-Asp (–RGD–) repeats, providing functional and structural versatility. The B30.2/SPRY domain facilitates protein–protein interactions in these E3s, while the COS domain mediates microtubule association.
The second subfamily (TRIM–SPRY) lacks these characteristic domains and demonstrates greater structural consistency among its members. This classification aligns with previously established domain-based categorizations of TRIM E3s. Additionally, RNF207, a RING-type RNF ligase with a Zn-finger B-box type and RING-type domain, is co-clustered with this family.
Multiple sequence alignment (MSA) of the RING8 family revealed the conservation of the RING domain, B-box type, and B-box C-terminal domain. Functional analysis indicated that this family is enriched in specific biological processes, including suppression of viral release by the host, innate immune response, and positive regulation of catabolic processes. Additionally, key molecular functions such as transcription coregulator activity, ubiquitin-protein ligase activity, and protein homodimerization activity are significantly enriched in this family.
The PDB contains 78 resolved structures, covering 16 of 18 RING8 E3 ligases. Among these, eight proteins are likely to function as standalone ligases, nine as components of complex ligases, and one remains unclassified. Examination of the E3–substrate interaction (ESI) network for this family identified 86 unique E3-specific substrates and 20 family-specific substrates. Additionally, a few small-molecule binders for TIF1A and TRIM33 were detected, which could potentially be developed into E3-targeting handles.
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).
