The cullin-ROC family of E3 ligases regulates the ubiquitylation of many substrates by assembling into multiple distinct E3 ligases. Each cullin uses a modular assembly to recruit different substrates to a common catalytic core by varying its substrate receptor. Cullin family members (green) from different organisms share similar mechanisms for assembling a multi-subunit complex to ubiquitylate specific substrate protein (light blue). An N-terminal domain interacts either directly with a protein motif (orange) present in substrate receptors (black) or via a linker (blue). Separately, a C-terminal domain binds with a small RING protein (ROC1 or ROC2, yellow) which recruits and allosterically activates an E2 enzyme (red) that transfers ubiquitin (Ub; color) to the substrate. Cullins are activated by the covalent conjugation with a ubiquitin-like modifier, NEDD8 (Nd8; purple). Human cells express an estimated 78 F-box proteins, 205 BTB proteins, about 90 DWD proteins and an estimated 50 BC-box proteins.