Cullin5based

Cullin5based refers to protein complexes in which the scaffold protein Cullin 5 forms the core of an E3 ubiquitin ligase assembly. In mammalian cells, Cullin‑RING ubiquitin ligases (CRLs) are modular machines that target specific substrates for ubiquitination and subsequent proteasomal degradation. Cullin5 is one of seven Cullin family members, distinguished by its ability to recruit the adaptor protein SOCS box‑containing proteins, such as SOCS1, SOCS2, and various ankyrin repeat proteins. The Cullin5 complex associates with the ubiquitin‑conjugating enzyme UbcH5 and the RING‑box protein RBX2, thereby catalyzing the transfer of ubiquitin from E2 to substrate proteins.

The principal functional role of Cullin5based ligases is regulation of phosphorylation‑dependent signaling cascades. For instance, SOCS3‑containing Cullin5 complexes target the activated Janus kinase 2 (JAK2) and signal transducers and activators of transcription (STATs) for ubiquitination, attenuating cytokine signaling. Other adaptors tether substrates such as p53, Notch intracellular domain, and various transcription factors, thereby modulating cell cycle arrest, apoptosis, and differentiation.

Dysregulation of Cullin5based ligases contributes to disease settings. Overexpression of SOCS proteins can suppress immune responses and promote tumor progression, whereas loss of Cullin5 function or mutations in associated adaptors lead to uncontrolled cytokine signaling and autoimmunity. Several small‑molecule inhibitors target the neddylation pathway that activates Cullin scaffolds, offering therapeutic potential in cancers where Cullin5based ubiquitination is aberrant.

Research has illuminated the structural organization of Cullin5 complexes, revealing distinct binding interfaces for adaptors and the catalytic core. This knowledge underpins the design of selective modulators that can interfere with specific substrate–ligase interactions without globally inhibiting CRLs, which remains an active area of drug discovery.