Dimer formation drives the activation of the cell death protease caspase 9
Dimer formation drives the activation of the cell death protease caspase 9
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DOI：
10.1073/pnas.231465798
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发表时间：
2001-12-04
影响因子：
11.1
通讯作者：
Salvesen, GS
中科院分区：
文献类型：
--
作者：
Renatus, M;Stennicke, HR;Salvesen, GS
诱导细胞凋亡的关键步骤是激活凋亡引发剂caspase 9。我们发现，在正常的生理浓度下，caspase 9主要是一个无活性的单体（酶原），其活性与二聚体有关。在用于晶体形成的高浓度下，caspase 9是二聚体，其结构在每个二聚体中显示出两种非常不同的活性位点构象。一个位点与其他半胱天酶的催化活性位点非常相似，而在第二个位点，“激活环”的排出破坏了催化机制。我们认为失活结构域类似于单体caspase 9。激活是由二聚体引起的，二聚体界面上的相互作用促进了激活环的重新定向。这些观察结果支持了一个模型，在这个模型中，Apaf-1的募集产生了高局部浓度的caspase 9，为二聚体诱导的激活提供了一条途径。
A critical step in the induction of apoptosis is the activation of the apoptotic initiator caspase 9. We show that at its normal physiological concentration, caspase 9 is primarily an inactive monomer (zymogen), and that activity is associated with a dimeric species. At the high concentrations used for crystal formation, caspase 9 is dimeric, and the structure reveals two very different active-site conformations within each dimer. One site closely resembles the catalytically competent sites of other caspases, whereas in the second, expulsion of the "activation loop" disrupts the catalytic machinery. We propose that the inactive domain resembles monomeric caspase 9. Activation is induced by dimerization, with interactions at the dimer interface promoting reorientation of the activation loop. These observations support a model in which recruitment by Apaf-1 creates high local concentrations of caspase 9 to provide a pathway for dimer-induced activation.