Rape Michael, Reddy Sashank K, Kirschner Marc W
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2006 Jan 13;124(1):89-103. doi: 10.1016/j.cell.2005.10.032.
The anaphase-promoting complex (APC) coordinates mitosis and G1 by sequentially promoting the degradation of key cell-cycle regulators. Following the degradation of its substrates in G1, the APC catalyzes the autoubiquitination of its E2 UbcH10. This stabilizes cyclin A and allows it to inactivate APC(Cdh1). How the APC establishes this complex temporal sequence of ubiquitinations, referred to as substrate ordering, is not understood. Here we show that substrate ordering depends on the relative processivity of substrate multiubiquitination by the APC. Processive substrates obtain ubiquitin chains in a single APC binding event. The multiubiquitination of distributive substrates requires multiple rounds of APC binding, which render it sensitive to lower APC concentrations, competition by processive substrates, and deubiquitination. Consequently, more processive substrates are preferentially multiubiquitinated in vitro and degraded earlier in vivo. The processivity of multiubiquitination is strongly influenced by the D box within the substrate, suggesting that substrate ordering is established by a mechanism intrinsic to APC and its substrates and similar to kinetic proofreading.
后期促进复合物（APC）通过依次促进关键细胞周期调节因子的降解来协调有丝分裂和G1期。在G1期其底物降解后，APC催化其E2泛素结合酶UbcH10的自身泛素化。这使细胞周期蛋白A稳定，并使其能够使APC（Cdh1）失活。APC如何建立这种复杂的泛素化时间序列，即所谓的底物排序，目前尚不清楚。在这里，我们表明底物排序取决于APC对底物多泛素化的相对持续性。持续性底物在单个APC结合事件中获得泛素链。分布式底物的多泛素化需要多轮APC结合，这使其对较低的APC浓度、持续性底物的竞争和去泛素化敏感。因此，在体外，更多的持续性底物优先进行多泛素化，并且在体内更早地被降解。多泛素化的持续性受到底物内D框的强烈影响，这表明底物排序是由APC及其底物固有的一种机制建立的，类似于动力学校对。
