The processivity of multiubiquitination by the APC determines the order of substrate degradation
The processivity of multiubiquitination by the APC determines the order of substrate degradation
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DOI：
10.1016/j.cell.2005.10.032
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发表时间：
2006-01-13
期刊：
影响因子：
64.5
通讯作者：
Kirschner, MW
中科院分区：
文献类型：
--
作者：
Rape, M;Reddy, SK;Kirschner, MW
后期促进复合物（APC）协调有丝分裂和G1通过依次促进关键细胞周期调节剂的降解。在G1中降解其底物后，APC催化其E2 UbcH10的autoubiquitination。这稳定了细胞周期蛋白A，并使其能够抑制ApC（Cdh 1）。APC如何建立这种复杂的泛素化时间序列（称为底物排序）尚不清楚。在这里，我们表明，基板订购取决于基板multiubiquitination的APC的相对持续性。加工底物在单个APC结合事件中获得泛素链。分布底物的多泛素化需要多轮APC结合，这使得它对较低的APC浓度、加工底物的竞争和去泛素化敏感。因此，更多的加工底物在体外优先被多泛素化，在体内降解更早。multiubiquitination的持续合成能力受到底物内D盒的强烈影响，这表明底物排序是由APC及其底物固有的机制建立的，类似于动力学校对。
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 multi ubiquitination 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.