Cullins

Cullins are a family of highly conserved scaffold proteins that form the core of the Cullin-RING ubiquitin ligases (CRLs), a large class of E3 ubiquitin ligases responsible for tagging proteins with ubiquitin to mark them for proteasomal degradation. In humans the Cullin family includes eight members: CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7 and CUL9. Each Cullin serves as a structural platform that coordinates a multi-subunit complex.

In a typical CRL, the Cullin scaffold binds a RING-finger protein such as RBX1, which recruits an E2 ubiquitin-conjugating enzyme. The N-terminal region of the Cullin associates with substrate receptors via adaptor proteins, creating a modular assembly that confers substrate specificity. Different Cullins assemble with distinct sets of adaptors and receptors, giving rise to various CRLs, such as SCF (Skp1-CUL1-F-box protein) complexes, CUL2-based ligases, CUL3-based ligases with BTB domain adaptors, and CUL4- or CUL5-containing ligases.

Activation and regulation of CRLs involve neddylation, the attachment of the ubiquitin-like modifier NEDD8 to a lysine residue on the Cullin. Neddylation enhances ligase activity, while deneddylation by the COP9 signalosome reduces activity, providing a rapid means to regulate substrate degradation in response to cellular cues.

Cullin-based ligases regulate a broad range of cellular processes, including cell cycle progression, DNA replication, transcription, and signaling pathways. Given their central role in protein turnover, Cullins and CRLs are implicated in development and disease; dysregulation or mutation of Cullins has been associated with various cancers and developmental disorders.