CUL1 (cullin 1) functions as the core scaffolding component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complexes, which mediate protein ubiquitination and subsequent proteasomal degradation 1. CUL1 serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits, with the functional specificity determined by the F-box protein substrate recognition component 1. The E3 ligase activity requires neddylation of the CUL1 subunit, and CAND1 mediates exchange of substrate recognition components 2. SCF complexes collaborate with ARIH1 in E3-E3 super-assemblies to ubiquitinate diverse substrates through a sophisticated mechanism where ARIH1's catalytic cysteine transfers ubiquitin to substrates bound to F-box proteins 3. CUL1 is critical for multiple cellular processes including cell cycle regulation, with SCF complexes targeting key proteins like CDKN1B/p27kip, CTNNB1, and NFKBIA for degradation 1. Disease relevance includes neurodevelopmental disorders, where CUL1 variants cause severe microcephaly and intellectual disability 4, and cancer, where CUL1 degradation by MARCHF8 stabilizes HPV E7 oncoprotein in head and neck cancer 5. The protein also regulates the Nrf1 stress response pathway through unconventional ubiquitination mechanisms 6.