Ubiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization.
Ubiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization.
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DOI：
10.1038/ncomms7718
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发表时间：
2015-04-24
影响因子：
16.6
通讯作者：
Chin, Jason W.
中科院分区：
文献类型：
--
作者：
Madrzak, Julia;Fiedler, Marc;Johnson, Christopher M.;Ewan, Richard;Knebel, Axel;Bienz, Mariann;Chin, Jason W.
紊乱将Wnt信号从质膜传递到不同的细胞质效应物。其信号传导活性取决于其DIX结构域，其经历头-尾聚合以组装信号体。DIX结构域在体内在多个赖氨酸处被泛素化，这可以被各种去泛素化酶（DUB）拮抗，包括减弱Wnt信号传导的CYLD肿瘤抑制因子。在此，我们通过遗传编码的正交保护与活化连接（GOPAL）产生毫克量的在两个赖氨酸（K54和K58）处单泛素化的纯人Dv 12 DIX结构域，以研究它们对DIX聚合的影响。我们发现，DIX在K54处的泛素化阻断了其在溶液中的聚合，而DIX 58-Ub仍然具有低聚能力。DUB分析鉴定了28种切割DIX-泛素缀合物的DUB，其中一半优选或特异于DIX 54-Ub，包括Cezanne和CYLD。因此，这些DUB具有促进Dvl聚合和信号体形成的潜力，而不是如先前对于CYLD所认为的那样拮抗它。 Wnt信号传递到细胞质需要通过Dishevelled（Dvl）的可逆聚合形成信号体。在这里，作者建立了Dvl DIX结构域的泛素化的功能后果，并确定了预测促进Dvl聚合的去泛素化酶。
Dishevelled relays Wnt signals from the plasma membrane to different cytoplasmic effectors. Its signalling activity depends on its DIX domain, which undergoes head-to-tail polymerization to assemble signalosomes. The DIX domain is ubiquitinated in vivo at multiple lysines, which can be antagonized by various deubiquitinases (DUBs) including the CYLD tumour suppressor that attenuates Wnt signalling. Here, we generate milligram quantities of pure human Dvl2 DIX domain mono-ubiquitinated at two lysines (K54 and K58) by genetically encoded orthogonal protection with activated ligation (GOPAL), to investigate their effect on DIX polymerization. We show that the ubiquitination of DIX at K54 blocks its polymerization in solution, whereas DIX58-Ub remains oligomerization-competent. DUB profiling identified 28 DUBs that cleave DIX-ubiquitin conjugates, half of which prefer, or are specific for, DIX54-Ub, including Cezanne and CYLD. These DUBs thus have the potential to promote Dvl polymerization and signalosome formation, rather than antagonize it as previously thought for CYLD. The relaying of Wnt signals to the cytoplasm requires the formation of signalosomes through the reversible polymerization of Dishevelled (Dvl). Here the authors establish the functional consequences of ubiquitination of the Dvl DIX domain and identify deubiquitinases predicted to promote Dvl polymerization.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1074/mcp.r110.003871
发表时间：
2011-05-01
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Lee, Min Jae;Lee, Byung-Hoon;Finley, Daniel
通讯作者：
Finley, Daniel
DOI：
10.1080/21513732.2014.885157
发表时间：
2014-01-02
期刊：
International Journal of Biodiversity Science Ecosystem Services & Management
影响因子：
--
作者：
de Groot, Rudolf S.;van Oudenhoven, Alexander P. E.
通讯作者：
van Oudenhoven, Alexander P. E.
影响因子：
56.9
作者：
Bilic, Josipa;Huang, Ya-Lin;Niehrs, Christof
通讯作者：
Niehrs, Christof
影响因子：
16.6
作者：
Hejjaoui, Mirva;Haj-Yahya, Mahmood;Lashuel, Hilal A.
通讯作者：
Lashuel, Hilal A.