Ubiquitin can be covalently linked to many cellular proteins by the ubiquitination process, which targets proteins for degradation by the 26S proteasome. Three components are involved in the target protein-ubiquitin conjugation process. Ubiquitin is first activated by forming a thiolester complex with the activation component E1; the activated ubiquitin is subsequently transferred to the ubiquitin-carrier protein E2, then from E2 to ubiquitin ligase E3 for final delivery to the epsilon-NH2 of the target protein lysine residue. Combinatorial interactions of different E2 and E3 proteins result in substrate specificity. Recent data suggest that activated E2 associates transiently with E3, and that the dissociation is a critical step for ubiqitination. Cullin homolog 1, the mammalian homolog of Cdc53 from yeast, is a molecular scaffold of the SCF E3 ubiquitin ligase protein complex. Thus, CUL1 and its family members function in ubiquitin dependent proteolysis. In particular, CUL1 has been shown to mediate ubiquitin dependent degradation of p21 Waf1/Cip1, cyclin D and IkappaB-alpha.
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