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

Abstract

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.