Posing the APC/C E3 Ubiquitin Ligase to Orchestrate Cell Division

• Published in: Trends in cell biology 2019-02, Vol.29 (2), p.117-134
• Main Authors: Watson, Edmond R., Brown, Nicholas G., Peters, Jan-Michael, Stark, Holger, Schulman, Brenda A.
• Format: Article
• Language: English
• Subjects: Anaphase; anaphase promoting complex/cyclosome; Anaphase-promoting complex; Anaphase-Promoting Complex-Cyclosome - chemistry; Anaphase-Promoting Complex-Cyclosome - metabolism; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Catalysis; Catalytic subunits; Cell division; cryo-electron microscopy; Cullin; Domains; E3 ligase; Humans; Mitosis; Models, Molecular; Molecular machines; Molecular structure; Protein Binding; Protein Conformation; Proteins; Regulatory mechanisms (biology); Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0962-8924; 1879-3088
• DOI: 10.1016/j.tcb.2018.09.007

The anaphase promoting complex/cyclosome (APC/C) E3 ligase controls mitosis and nonmitotic pathways through interactions with proteins that coordinate ubiquitylation. Since the discovery that the catalytic subunits of APC/C are conformationally dynamic cullin and RING proteins, many unexpected and intricate regulatory mechanisms have emerged. Here, we review structural knowledge of this regulation, focusing on: (i) coactivators, E2 ubiquitin (Ub)-conjugating enzymes, and inhibitors engage or influence multiple sites on APC/C including the cullin–RING catalytic core; and (ii) the outcomes of these interactions rely on mobility of coactivators and cullin–RING domains, which permits distinct conformations specifying different functions. Thus, APC/C is not simply an interaction hub, but is instead a dynamic, multifunctional molecular machine whose structure is remodeled by binding partners to achieve temporal ubiquitylation regulating cell division. APC/C is a massive, 1.2-MDa multiprotein E3 ligase comprised of scaffolding and substrate-binding modules, and a cullin–RING catalytic core. Recent technical advances have enabled reconstituting, assaying, and visualizing molecular mechanisms of recombinant APC/C E3 by cryo-EM in numerous states: before and after phosphorylation, and in complexes with substrate-bound coactivators, E2s, and inhibitors. The data collectively show remarkable conformational changes correlating with distinct mechanisms of activation, ubiquitylation, and inhibition. In particular, the mobility of the cullin and RING catalytic domains, taken together with multisite binding by APC/C partners, enables their differential capture and positioning to temporally control ubiquitylation-dependent steps in cell division.