The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities.
The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities.
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DOI：
10.1038/ncomms13565
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发表时间：
2016-11-24
影响因子：
16.6
通讯作者：
Bratton, Shawn B.
中科院分区：
文献类型：
--
作者：
Wu, Chu-Chiao;Lee, Sunhee;Malladi, Srinivas;Chen, Miao-Der;Mastrandrea, Nicholas J.;Zhang, Zhiwen;Bratton, Shawn B.
根据Dogma的说法，启动子caspase是通过邻近诱导的同源二聚来激活的，但一些研究推测，在细胞凋亡过程中，caspase-9可能会与APAF-1凋亡体形成一个全酶。利用几种生化方法，包括一种新的位点特异性交联技术，我们提供了第一个直接证据，证明前天冬氨酸氨基转移酶-9在凋亡体内同源二聚，显著增加了它对复合体的亲和力，并诱导了Asp-315的选择性分子内切割。然而，值得注意的是，proaspase-9也可以通过其小亚基与APAF-1中的nod结构域结合，导致形成异源二聚体，从而更有效地激活proaspase-3。切割后，caspase-9-p35/p12中的亚基间连接子(以及相关的构象变化)抑制了其形成同源和异源二聚体的能力，但caspase-3在Asp-330处的反馈切割完全移除了连接子，并部分恢复了caspase-9-p35/p10的活性。因此，凋亡体介导caspase-9同源和异源二聚体的形成，这两种二聚体都受到切割的影响，并对其整体功能做出贡献。凋亡启动子caspase被认为是通过同源二聚化被激活的，但这一点仍然存在争议。在这里，作者证明了caspase-9可以在APAF-1凋亡体中采用两种不同的构象，每种构象都具有不同的性质，有助于复合体的整体功能。
According to dogma, initiator caspases are activated through proximity-induced homodimerization, but some studies infer that during apoptosis caspase-9 may instead form a holoenzyme with the Apaf-1 apoptosome. Using several biochemical approaches, including a novel site-specific crosslinking technique, we provide the first direct evidence that procaspase-9 homodimerizes within the apoptosome, markedly increasing its avidity for the complex and inducing selective intramolecular cleavage at Asp-315. Remarkably, however, procaspase-9 could also bind via its small subunit to the NOD domain in Apaf-1, resulting in the formation of a heterodimer that more efficiently activated procaspase-3. Following cleavage, the intersubunit linker (and associated conformational changes) in caspase-9-p35/p12 inhibited its ability to form homo- and heterodimers, but feedback cleavage by caspase-3 at Asp-330 removed the linker entirely and partially restored activity to caspase-9-p35/p10. Thus, the apoptosome mediates the formation of caspase-9 homo- and heterodimers, both of which are impacted by cleavage and contribute to its overall function. Apoptotic initiator caspases are thought to be activated through homodimerization but this remains controversial. Here the authors demonstrate that caspase-9 can adopt two distinct conformations within the Apaf-1 apoptosome, each with distinct properties that contribute to the overall function of the complex.
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Apaf-1 凋亡体激活 caspase-9 的分子决定因素。
DOI：
10.1073/pnas.1418000111
发表时间：
2014-11-18
影响因子：
11.1
作者：
Hu, Qi;Wu, Di;Shi, Yigong
通讯作者：
Shi, Yigong
工程二聚体caspase-9：重新评估caspase激活的诱导接近模型。
影响因子：
9.8
作者：
Chao, Y;Shiozaki, EN;Srinivasula, SM;Rigotti, DJ;Fairman, R;Shi, YG
通讯作者：
Shi, YG
影响因子：
11.4
作者：
Malladi, Srinivas;Challa-Malladi, Madhavi;Bratton, Shawn B.
通讯作者：
Bratton, Shawn B.
影响因子：
64.8
作者：
Qin, HX;Srinivasula, SM;Shi, YG
通讯作者：
Shi, YG
影响因子：
11.4
作者：
Deveraux, QL;Leo, E;Reed, JC
通讯作者：
Reed, JC