Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication
Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication
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DOI：
10.1038/35107009
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发表时间：
2001-11-29
期刊：
影响因子：
64.8
通讯作者：
Tyers, M
中科院分区：
文献类型：
--
作者：
Nash, P;Tang, XJ;Tyers, M
SCF泛素连接酶通过称为F - box蛋白的衔接子亚基，将磷酸化底物作为目标进行泛素依赖性蛋白水解。F - box蛋白Cdc4在G1期晚期捕获细胞周期蛋白依赖性激酶抑制剂Sic1的磷酸化形式以进行泛素化，这是DNA复制开始所必需的事件。Cdc4的WD40重复结构域以高亲和力与一个共有磷酸肽基序（Cdc4磷酸化降解子，CPD）结合，然而Sic1自身有许多次优的CPD基序，它们协同作用以介导Cdc4结合。Sic1中较弱的CPD位点建立了一个磷酸化阈值，该阈值延迟了体内的降解，从而确定了确保适当DNA复制所需的最短G1期。多位点磷酸化可能是在受调控的蛋白质 - 蛋白质相互作用中设定阈值的一种更普遍的机制。
SCF ubiquitin ligases target phosphorylated substrates for ubiquitin-dependent proteolysis by means of adapter subunits called F-box proteins. The F-box protein Cdc4 captures phosphorylated forms of the cyclin-dependent kinase inhibitor Sic1 for ubiquitination in late G1 phase, an event necessary for the onset of DNA replication. The WD40 repeat domain of Cdc4 binds with high affinity to a consensus phosphopeptide motif (the Cdc4 phospho-degron, CPD), yet Sic1 itself has many sub-optimal CPD motifs that act in concert to mediate Cdc4 binding. The weak CPD sites in Sic1 establish a phosphorylation threshold that delays degradation in vivo, and thereby establishes a minimal G1 phase period needed to ensure proper DNA replication. Multisite phosphorylation may be a more general mechanism to set thresholds in regulated protein-protein interactions.