Molecular Cell

control of numerous cellular processes. The final step in ubiqui- tor’s substrate-recruiting function. Consistent with this possi-tination is catalyzed by a ubiquitin ligase or E3, which facilitates the transfer of an activated ubiquitin from a ubiquitin-conjugating enzyme (E2) to a lysine on a specific substrate or on ubiquitin itself, thereby forming ubiquitin chains that target the substrate for degradation by the proteasome. The anaphase-promoting complex/cyclosome (APC/C) is a multisubunit E3 required for the initiation of anaphase and the completion of mitosis in all eu-karyotic cells (Peters, 2006; Sullivan and Morgan, 2007b; Thorn-ton and Toczyski, 2006). Although themost important substrates of the APC/C are securin and the mitotic cyclins (Thornton and Toczyski, 2003), the APC/C ubiquitinates numerous additional substrates involved in late mitotic events. Most of these bility, electron microscopic (EM) analyses suggest that the APC/C adopts a different conformation in the presence of Cdh1 (Dube et al., 2005). Two lines of evidence suggest that substrate binding to the APC/C is not mediated entirely by the activator protein. First, there is evidence for a direct, low-affinity interaction between substrate and the APC/C in the absence of activator (Eytan et al., 2006; Yamano et al., 2004). Second, the APC/C subunit Doc1 promotes substrate binding through a mechanism that appears to be independent of activator binding (Passmore et al., 2003). Removal of Doc1 increases the rate of substrate dissociation from the active site, resulting in a decrease inAnalysis of Activator-Bindin Supports aCooperativeSu