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 and 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 suggests that activated E2 associates transiently with E3, and the dissociation is a critical step for ubiquitination. S phase kinase-associated protein 1 is a critical scaffold protein of the Skp1/CUL1/F-box E3 ubiquitin ligase protein complex. Various F-box proteins mediate an interaction with Skp1, via their defining and conserved domain of 40 amino acids, and with substrates to be ubiquitinated.
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