Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system.
Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system.
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DOI：
10.1038/ncomms10239
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发表时间：
2016-01-06
影响因子：
16.6
通讯作者：
Tompa P
中科院分区：
文献类型：
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作者：
Guharoy M;Bhowmick P;Sallam M;Tompa P
特定信号（degrons）调节由泛素-蛋白酶体系统介导的蛋白质周转。在这里，我们系统地分析了已知的degron，并提出了一个三方模型，包括：(1)一个初级degron（肽基序），它指定了同源E3泛素连接酶对底物的识别，(2)由一个或多个邻近的泛素化赖氨酸组成的二级位点，(3)一个结构紊乱的片段，它启动了26S蛋白酶体的底物展开。初级退化序列在同源物中是保守的，发生在结构紊乱的区域，经历e3诱导的结合折叠。翻译后修饰可以将初级降解转变为e3结合能力状态，从而将降解与信号通路结合起来。降解相关赖氨酸往往位于无序的片段中，这些片段也通过有效的蛋白酶体参与启动底物降解。许多特征突变和替代同工异构体与废除脱菌成分涉及疾病。这些影响是由于蛋白质稳定性和相互作用组重新布线的增加。降解的分布特性保证了降解的调节、特异性和组合控制。降解因子是蛋白质内的决定因子，它通过泛素蛋白酶体系统指导程序性降解。在这里，作者提出了一个由三部分组成的降解结构，其中包含一个e3连接酶识别基序，一个泛素化位点和一个启动降解的无序位点。
Specific signals (degrons) regulate protein turnover mediated by the ubiquitin-proteasome system. Here we systematically analyse known degrons and propose a tripartite model comprising the following: (1) a primary degron (peptide motif) that specifies substrate recognition by cognate E3 ubiquitin ligases, (2) secondary site(s) comprising a single or multiple neighbouring ubiquitinated lysine(s) and (3) a structurally disordered segment that initiates substrate unfolding at the 26S proteasome. Primary degron sequences are conserved among orthologues and occur in structurally disordered regions that undergo E3-induced folding-on-binding. Posttranslational modifications can switch primary degrons into E3-binding-competent states, thereby integrating degradation with signalling pathways. Degradation-linked lysines tend to be located within disordered segments that also initiate substrate degradation by effective proteasomal engagement. Many characterized mutations and alternative isoforms with abrogated degron components are implicated in disease. These effects result from increased protein stability and interactome rewiring. The distributed nature of degrons ensures regulation, specificity and combinatorial control of degradation. Degrons are determinants within proteins that direct programmed degradation by the ubiquitinproteasome system. Here, the authors propose a three-part degron architecture which contains an E3-ligase recognition motif, a ubiquitination site(s), and a disordered site to initiate degradation.