Cullin2

Cullin-2 (CUL2) is a scaffold protein that forms the backbone of a subset of Cullin-RING E3 ubiquitin ligases (CRLs), known as CRL2 complexes. It is a member of the cullin family and plays a central role in assembling ubiquitin ligase machinery that tags specific substrates for degradation by the proteasome.

CRL2 complexes consist of CUL2 bound at the N-terminus to adaptor proteins such as Elongin B and Elongin C, and at the C-terminus to the RING finger protein ROC1 (RBX1). The substrate receptor is recruited via a SOCS box or a VHL box, connecting the CRL2 core to specific target proteins. This modular architecture allows CRL2 to recognize a variety of substrates through different SOCS-box or VHL-box adaptors.

One well-characterized CRL2 complex is CRL2^VHL, which targets hypoxia-inducible factor 1-alpha (HIF-1α) for ubiquitination under normoxic conditions, leading to its degradation. Other CRL2 complexes incorporate different SOCS-box proteins or related receptors, broadening the range of substrates that can be regulated by this ligase.

Regulation occurs through cullin neddylation: CUL2 is activated by conjugation of NEDD8, which promotes ubiquitin transfer, and is inactivated by deneddylation via the COP9 signalosome. This dynamic control modulates the activity of CRL2 toward its substrates.

Biological significance includes regulation of hypoxia responses, angiogenesis, development, and metabolism. Dysregulation of CRL2 pathways is linked to disease, and mutations in the VHL component are associated with von Hippel-Lindau disease, highlighting the importance of CUL2-containing ligases in cellular homeostasis. CUL2 is evolutionarily conserved across eukaryotes.