Who with whom: functional coordination of E2 enzymes by RING E3 ligases during poly-ubiquitylation.
Who with whom: functional coordination of E2 enzymes by RING E3 ligases during poly-ubiquitylation.
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谁与谁：在多泛素化过程中，环E3连接酶对E2酶的功能协调。
DOI：
10.15252/embj.2020104863
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发表时间：
2020-11-16
期刊：
影响因子：
--
通讯作者：
Klevit RE
中科院分区：
文献类型：
--
作者：
Lips C;Ritterhoff T;Weber A;Janowska MK;Mustroph M;Sommer T;Klevit RE
用多聚泛素链修饰蛋白质是参与无数细胞途径的关键过程。链合成需要两个步骤：底物修饰与泛素（引发），然后重复泛素-到-泛素连接（延伸）。RING-型E3连接酶与特异性引发和延伸E2酶协同催化这两种反应。我们提供了在蛋白质质量控制过程中对多聚泛素化的动力学见解，表明引发是由酵母ERAD RING E3连接酶Hrd 1和Doa 10指导的蛋白质降解的速率决定步骤。Doa 10与专用启动E2、Ubc 6配合，而两个E3都使用Ubc 7进行延伸。在这里，我们提供了直接的证据，Hrd 1使用Ubc 7也启动。我们发现Ubc 6具有异常高的基础活性，不需要E3的强烈刺激。Doa 10利用此属性在预充期间与Ubc 6而不是Ubc 7配对。我们的工作不仅阐明了ERAD中特定E2/E3相互作用的机制，而且还为理解RING E3如何具有与其首选E2配对的特性提供了基础。ERAD E3（Hrd 1，Doa 10）和E2（Ubc 6，Ubc 7）酶的动力学分析揭示了泛素链引发步骤的限速性质，以及引发过程中这些E3各自E2偏好的分子基础。
Protein modification with poly‐ubiquitin chains is a crucial process involved in a myriad of cellular pathways. Chain synthesis requires two steps: substrate modification with ubiquitin (priming) followed by repetitive ubiquitin‐to‐ubiquitin attachment (elongation). RING‐type E3 ligases catalyze both reactions in collaboration with specific priming and elongating E2 enzymes. We provide kinetic insight into poly‐ubiquitylation during protein quality control by showing that priming is the rate‐determining step in protein degradation as directed by the yeast ERAD RING E3 ligases, Hrd1 and Doa10. Doa10 cooperates with the dedicated priming E2, Ubc6, while both E3s use Ubc7 for elongation. Here, we provide direct evidence that Hrd1 uses Ubc7 also for priming. We found that Ubc6 has an unusually high basal activity that does not require strong stimulation from an E3. Doa10 exploits this property to pair with Ubc6 over Ubc7 during priming. Our work not only illuminates the mechanisms of specific E2/E3 interplay in ERAD, but also offers a basis to understand how RING E3s may have properties that are tailored to pair with their preferred E2s. Kinetic analyses of ERAD E3 (Hrd1, Doa10) and E2 (Ubc6, Ubc7) enzymes reveal the rate‐limiting nature of the ubiquitin chain priming step, and the molecular basis for respective E2 preferences of these E3s during priming.
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影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
DOI：
10.1074/jbc.m112.352484
发表时间：
2012-08-24
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Emberley ED;Mosadeghi R;Deshaies RJ
通讯作者：
Deshaies RJ
影响因子：
16
作者：
Brown, Nicholas G.;Watson, Edmond R.;Weissmann, Florian;Jarvis, Marc A.;VanderLinden, Ryan;Grace, Christy R. R.;Frye, Jeremiah J.;Qiao, Renping;Dube, Prakash;Petzold, Georg;Cho, Shein Ei;Alsharif, Omar;Bao, Ju;Davidson, Iain F.;Zheng, Jie J.;Nourse, Amanda;Kurinov, Igor;Peters, Jan-Michael;Stark, Holger;Schulman, Brenda A.
通讯作者：
Schulman, Brenda A.
影响因子：
64.5
作者：
FINLEY, D;OZKAYNAK, E;VARSHAVSKY, A
通讯作者：
VARSHAVSKY, A
影响因子：
16
作者：
Bagola, Katrin;von Delbrueck, Maximilian;Sommer, Thomas
通讯作者：
Sommer, Thomas