The anaphase promoting complex/cyclosome: a machine designed to destroy

Key Points

  • The anaphase promoting complex/cyclosome (APC/C) is a 1.5-MDa ubiquitin ligase complex that initiates sister-chromatid separation and exit from mitosis by targeting cyclin B and securin for destruction by the 26S proteasome.

  • APC/C activity is also indirectly required for DNA replication, because APC/C-mediated cyclin degradation leads to the inactivation of cyclin-dependent kinase-1 (Cdk1), which is a prerequisite for the assembly of pre-replication complexes.

  • APC/C is activated by proteins of the Cdc20/Cdh1 family. The interaction between APC/C and its co-activators is tightly controlled by phosphorylation and is restricted to mitosis and G1 phase.

  • In addition, APC/C activity can be restrained by a number of inhibitory proteins. Mad2 and BubR1 inhibit APC/C during spindle assembly and thereby prevent precocious initiation of anaphase and exit from mitosis. Members of the early mitotic inhibitor-1 (EMI1)/regulator of cyclin A-1 (RCA1) family inhibit APC/C from S phase until early mitosis and during meiosis in vertebrate eggs.

  • Co-activator proteins activate APC/C by facilitating the recruitment of substrates. All known APC/C co-activators contain a propeller-shaped WD40 domain that interacts with a recognition element in APC/C substrates and is known as the destruction box (D-box).

  • Co-activators are required but not sufficient for substrate recognition because the APC/C subunit Doc1 is also needed for this process. Several observations suggest that the D-box of substrates might interact with both co-activators and APC/C subunits to form a ternary complex in which substrate ubiquitylation occurs.

Abstract

The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. Recent discoveries have revealed an unexpected multitude of mechanisms that control APC/C activity, and have provided a first insight into how this unusual ubiquitin ligase recognizes its substrates.

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Figure 1: The three-dimensional structure of APC/C.
Figure 2: Regulation of anaphase and mitotic exit by APC/CCdc20.
Figure 3: Activation of APC/C by Cdc20 and Cdh1 during the cell cycle.
Figure 4: Inactivation of APC/CCdh1 at the transition from G1 to S phase.
Figure 5: Activation of Mad2 at unattached kinetochores.

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Acknowledgements

I am grateful to A. Musacchio and members of my group for helpful discussions and to H. Stark and D. Barford for providing images. Research in my laboratory is supported by Boehringer Ingelheim, the European Molecular Biology Organization, the 6th Framework Programme of the European Union via the Integrated Project MitoCheck, and the European Science Foundation and the Austrian Science Fund via the EuroDYNA Programme.

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Glossary

Ubiquitin ligase (E3)

The third enzyme in a series — the first two are designated ubiquitin-activating (E1) and ubiquitin-conjugating (E2) — that is responsible for the ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating the ubiquitylation of selected substrates.

Polyubiquitin chains

Protein assemblies that are composed of several copies of the small protein ubiquitin. The ubiquitin residues are covalently attached to each other through isopeptide bonds.

26S proteasome

A large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that carries the catalytic activity and two regulatory 19S particles.

Cyclin-dependent kinase

(Cdk). A protein kinase that has activity that depends on an association with a cyclin subunit. Cdks are essential for DNA replication and entry into mitosis.

Ubiquitin-activating (E1) enzyme

An enzyme that activates the C-terminal glycine residue of the small protein ubiquitin, allowing it to form a high-energy thioester bond to a specific cysteine residue of the E1. E1 then transfers this activated form of ubiquitin onto ubiquitin-conjugating (E2) enzymes.

Ubiquitin-conjugating (E2) enzyme

An enzyme that forms a thioester bond with a ubiquitin residue, which is transferred to the E2 enzyme from ubiquitin-activating (E1) enzyme. E2 uses the high energy from the thioester bond to generate an isopeptide bond between the ubiquitin residue and a lysine residue on a substrate protein.

SCF

A multisubunit ubiquitin ligase complex that is composed of two scaffolding subunits (cullin and Skp1), a RING-finger subunit that binds ubiquitin-conjugating (E2) enzymes and one of many F-box subunits that recruit substrates.

C-box

A sequence element (consensus DRF/YIPXR) that was first found in the N-terminal region of Cdc20. It is conserved in all known APC/C co-activators.

IR-tail

A sequence element (consensus IR) at the extreme C terminus of APC/C co-activators and the APC/C subunit Doc1.

WD40 domain

A propeller-shaped protein domain that is composed of sequence repeats that are 40-amino-acid residues long and contain tryptophan (W) and aspartate (D) residues in conserved positions. In most cases, seven WD40 repeats fold into a seven-bladed propeller structure.

D-box

(Destruction-box). A sequence element (consensus RXXLXXXN) that was first discovered in the N terminus of mitotic cyclins that is required for their destruction. D-boxes can be recognized by APC/CCdc20 and by APC/CCdh1.

KEN-box

A sequence element (consensus KEN) that is present in many APC/C substrates. KEN-boxes are preferentially, but not exclusively, recognized by APC/CCdh1.

Cullin

A member of the cullin family of proteins. All cullins are subunits of SCF ubiquitin ligases or APC/C, and they bind to a RING-finger subunit via a conserved cullin domain.

RING finger

A small protein domain that binds two atoms of zinc (consensus CXXCX(9–39)CX(1–3)HX(2–3)C/HXXCX(4–48)CXXC). Many RING-finger domains interact with ubiquitin-conjugating (E2) enzymes and have ubiquitin ligase (E3) activity.

TPR domain

(Tetratrico peptide repeat domain). A 34-amino-acid sequence repeat, clusters of which fold into a helical structure and mediate protein–protein interactions.

Checkpoint

A surveillance mechanism that delays progression through the cell cycle if processes such as DNA replication and spindle assembly have not been completed.

Kinetochore

A large proteinacous structure that assembles on centromeric DNA, binds the plus ends of microtubules and thereby connects chromosomes with spindle poles.

Quiescence

The physiological state of cells that are not in the cell cycle.

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Peters, J. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7, 644–656 (2006). https://doi.org/10.1038/nrm1988

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