- 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 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.
- 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. Another example is Parkin, a RING-type ligase involved in mitochondrial quality control, mutations of which are linked to familial forms of Parkinson’s disease.
- 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 RING ligases such as CRBN and VHL, redirecting them to degrade disease-causing proteins.
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