The RING2 family comprises eight membrane-associated RING-CH-type Zn-finger E3 ligases. Members of this family are characterized by a catalytic Zn-finger RING-CH type domain (IPR011016). The RING-CH domain exhibits a distinctive structure compared to the classical RING finger, featuring cysteine and histidine residues at the fourth and fifth zinc-coordinating positions.
This RING family is homogeneous and organized into a single subfamily. All the members share a typical structural organization, featuring an N-terminal cytosolic catalytic RING-CH type domain followed by a transmembrane (TM) region containing two TM helices, except for MARCH5 (contains 4 TM helices).
The MSA for this family reveals conservation of both the N-terminal RING domain and TM regions. The longer MARCH E3 ligases (>700 residues; MARH6, MARH7, MARCH10) co-cluster with the RING7 family and form a separate sub-group. As integral membrane proteins, these ligases are predominantly localized to endosomes, lysosomes, and the plasma membrane, where they regulate membrane protein ubiquitination and degradation.
MARH1 regulates insulin receptor signaling and mediates lysosome-dependent degradation of MHC class II molecules. The PDB resource provides one structure covering 1 out of 8 RING2 proteins. RING2 family members also predominantly function as standalone E3 ligases. Analysis of the ESI network for this family revealed 73 unique E3-specific substrates and 554 family-specific substrates. No small molecules or E3 binders are found to target the MARCH 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).
