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  • How does APC C recognize


    How does APC/C recognize its substrates and catalyze their ubiquitylation? How are the outcomes and timing of these activities regulated? These questions have driven a decade of structural studies that begin to explain how APC/C interacts with coactivators, substrates, and E2s, and how these interactions are tightly controlled by phosphorylation and inhibitory proteins to prevent premature cell division and collateral catastrophic consequences like HC-030031 (reviewed in 13, 14). Detailed insights into the stepwise regulation of APC/C throughout the cell cycle have come in the last few years from advances in generating recombinant multiprotein complexes and cryo-electron microscopy (cryo-EM). Structural details provided by cryo-EM reconstructions of APC/C complexes, and X-ray crystallography and NMR data on subcomplexes, as well as enzymology of ubiquitylation by wild-type and mutant versions of recombinant APC/C, have been described in recent excellent reviews 15, 34. However, we now understand that APC/C undergoes striking conformational changes accompanying its assembly into distinct complexes, as many recent structural studies have also shown that the ability of APC/C to perform different activities depends on rotation of coactivators, and on cullin and RING subunits transitioning from an intertwined inactive unit into conformationally mobile appendages 19, 20, 21, 24 that bind and are harnessed by different substrates, E2s, and inhibitors into distinct conformations specifying particular functions. Here, we summarize overall structural features of human APC/C, focusing on the emerging understanding of how its different conformations are achieved to establish regulation.
    Overall APC/C Organization Early EM and other studies of APC/C from several organisms revealed that APC/C is formed from modules that together adopt an overall curved structure around a central cavity displaying flexibly tethered protein binding domains 24, 35, 36, 37, 38, 39, 40, 41, 42, 43. These flexible domains recruit, and in turn are positioned by, APC/C’s many binding partners including substrates and the E2 enzymes that modify them (Figure 1 and Box 1). This architecture both juxtaposes the binding partners of APC/C, and enables a remarkable spectrum of conformations establishing the functions of this E3 ligase. The majority of APC/C subunits form a giant scaffold, which was originally named the arc lamp, based on its shape when viewing APC/C from one side (Figure 1 and Box 1) [24]. The scaffold consists of two modules: the TPR lobe resembles the curved post and lamp, and the platform resembles the base supporting the arched lamp-post. Although this visual analogy lacked functional relevance, it did reveal the organization that enables concentrating the two functional modules – the substrate recognition module (either CDC20 or CDH1 coactivator and in many cases also the core subunit APC10) and a catalytic module (i.e., the cullin–RING catalytic core consisting of the cullin subunit APC2 and its associated RING partner APC11) – within the central cavity through their respective interactions inside the TPR lobe and platform ([24]; reviewed in [15]).