RING Finger Ubiquitin Ligase

• RING finger ubiquitin ligases are a major class of E3 ubiquitin ligases that mediate protein ubiquitination within the ubiquitin–proteasome system. 
• The term “RING” comes from “Really Interesting New Gene”, the name first given to the motif when it was discovered. The RING finger domain is a specialized type of zinc-binding domain characterized by a conserved arrangement of cysteine and histidine residues that coordinate two zinc ions in a “cross-brace” structure. This compact fold stabilizes the domain and is essential for binding to ubiquitin-conjugating enzymes (E2s) and for the transfer of ubiquitin to substrates.
• Unlike HECT-type ligases, which form a covalent intermediate with ubiquitin, RING ligases do not directly bind ubiquitin in a covalent manner during the transfer process. Instead, they act as molecular scaffolds, bringing the ubiquitin-loaded E2 (E2~Ub) enzyme into close proximity with the substrate protein. Many RING domains also make non‑covalent contacts with the E2~Ub complex to orient the thioester bond for efficient transfer.
• By positioning the E2 and the substrate correctly, RING ligases facilitate the direct transfer of ubiquitin from the E2 to a lysine residue (or the N-terminus) of the substrate. This mechanism allows for rapid and efficient ubiquitination, and in many cases enables the assembly of ubiquitin chains of specific linkage types.
• RING ligases are extremely diverse and constitute the largest group of E3 ligases in eukaryotes. In humans, more than 600 E3 ligases have been identified, and the majority belong to the RING-type family. They can exist as single polypeptides (single-subunit ligases, e.g., MDM2) or as components of large multi-subunit complexes that provide modular substrate recognition (e.g., the SCF complex [Skp1–Cullin–F-box] and the APC/C [Anaphase-Promoting Complex/Cyclosome]). This structural versatility allows RING ligases to regulate an enormous range of cellular proteins.
• Functionally, RING finger ligases control virtually every aspect of cell biology. They regulate cell cycle progression by marking cyclins and checkpoint regulators for degradation. They are essential for DNA repair and replication, where they modify repair factors and histones. In the immune system, RING ligases help shape innate and adaptive responses, while in neurons they regulate synaptic plasticity and protein quality control. One of the most studied RING ligases is MDM2, which ubiquitinates the tumor suppressor protein p53, tightly controlling its stability and activity.
• Because of their central role in cellular regulation, defects in RING ligases are associated with a wide range of diseases, including cancer, neurodegeneration, immune disorders, and infectious diseases. Many viruses encode their own RING-like proteins or hijack host RING ligases to subvert cellular defenses. From a therapeutic standpoint, RING ligases have become attractive drug targets. In addition, the emerging technology of PROTACs (proteolysis-targeting chimeras) specifically exploits Cullin–RING ligase complexes such as CRL4^CRBN and CRL2^VHL. CRBN and VHL themselves are substrate receptors, not RING-domain proteins; the RING function in these complexes is provided by RBX1/RBX2. PROTACs redirect these endogenous CRL complexes to degrade disease-causing proteins.

Single-Chain RING Ligases:

• MDM2 (targets p53)
• c-Cbl (targets RTKs)
• BRCA1/BARD1 (DNA repair)
• TRIM family (e.g., TRIM21, TRIM25)
• MARCH family (e.g., MARCH1 through MARCH11)
• TRAF family (e.g., TRAF2, TRAF6)
• IAP family (e.g., XIAP, cIAP1, cIAP2)
• RNF family (e.g., RNF4, RNF8, RNF168)

Multi-Subunit Cullin-RING Ligases (CRLs):

• SCF Complexes (CRL1): Core components RBX1 + Cullin 1 + Skp1 + F-box adapter (~70 F-box proteins like -TrCP, SKP2, FBW7).
• CRL2 / Von Hippel-Lindau (VHL): Targets HIF-1.
• CRL3 / Keap1: Targets Nrf2 (oxidative stress response).
• CRL4 / Cereblon (CRBN): Target of immunomodulatory drugs (IMiDs like lenalidomide) and PROTACs.
• APC/C (Anaphase-Promoting Complex): Multi-protein mitotic ligase operating with Cdc20 or Cdh1 co-activators.

References/Further reading:

• Metzger, M.B., et al., 2014. RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta. 2014 Jan;1843(1):47-60. DOI: 10.1016/j.bbamcr.2013.05.026, PMID: 23747565, PMCID: PMC4109693, Google Scholar

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Last updated: 10th August 2026