Cullin-2 (CUL2)

Cullin-2 is a member of the Cullin protein family and acts as a scaffold for assembling multi-protein E3 ubiquitin ligase complexes, specifically the CRL2 (Cullin-RING Ligase 2) complexes[1][3]. These complexes consist of CUL2, the RING-box protein RBX1, adaptor proteins Elongin B/C, and substrate-specific recognition proteins, most notably the von Hippel-Lindau tumor suppressor (VHL)[1][2][3]. CRL2 complexes are involved in the targeted ubiquitination and proteasomal degradation of cellular substrates, with the degradation of hypoxia-inducible factor 1-alpha (HIF1α) being the most well characterized and clinically significant process[1][2][3]. Disruption of the VHL-CUL2 interaction is associated with cancer through stabilization of HIF1α, and CUL2-based E3 ligase activity also plays critical roles in development, germline maintenance, and in cellular responses to viral infection[1][3]. Drug discovery efforts have targeted CRL2 directly and indirectly, with the most significant pharmaceutical strategies involving the use of molecules such as PROTACs (which hijack CRL2^VHL for targeted protein degradation) and inhibitors of NEDD8 E1 activating enzyme (which block CRL2 activation)[1][3].

Other names

CUL2Cullin 2

Recruitment and ubiquitination of target proteins for proteasomal degradation via formation of CRL2 E3 ligase complexes PROTACs: Small molecules that redirect E3 ligase activity by bridging a target protein to the CRL2 complex, promoting its ubiquitination and degradation Nedd8-activating enzyme inhibition: prevents neddylation of CUL2, suppressing ligase activity