Cullin2based

Cullin-2based refers to a subset of Cullin-RING ubiquitin ligases (CRLs) in which Cullin-2 serves as the scaffold for assembling the ubiquitin-proteasome degradation machinery. In these complexes, Cullin-2 coordinates with the RING finger protein RBX1, the Elongin B and Elongin C adaptors, and a substrate receptor that binds target proteins. The substrate receptor typically contains a motif that binds Elongin B/C, enabling recruitment to the Cul-2 scaffold; many receptors within this family are described as VHL-box containing proteins, with the classic example being the von Hippel-Lindau (VHL) tumor suppressor that specifies a CRL2^VHL complex.

Functionally, Cullin-2-based ligases act as E3 ubiquitin ligases that catalyze the transfer of ubiquitin from an E2 enzyme to chosen substrates, marking them for proteasomal degradation. Substrate recognition is determined by the receptor component, allowing a diverse range of targets to be processed by different CRL2 complexes. The most well-characterized example is CRL2^VHL, which targets hypoxia-inducible factor α (HIF-α) for degradation under normal oxygen conditions; under low oxygen, HIF-α is stabilized and activates hypoxia-responsive gene expression.

Regulation of CRL2 complexes mirrors other CRLs. Activity is controlled by neddylation of Cullin-2 with NEDD8, which activates the ligase, and by deneddylation via the COP9 signalosome. Availability of adaptor proteins and substrate receptor turnover also influence assembly and function.

Clinical and research relevance arises from CRL2’s roles in development, metabolism, and stress responses, and from diseases linked to disrupted CRL2 function, such as von Hippel-Lindau disease. Inhibitors targeting the NEDD8 pathway or specific CRL2 components are investigated for cancer therapy.