ClpP: A structurally dynamic protease regulated by AAA+ proteins
ClpP: A structurally dynamic protease regulated by AAA+ proteins
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DOI：
10.1016/j.jsb.2012.05.003
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发表时间：
2012-08-01
影响因子：
3
通讯作者：
Ortega, Joaquin
中科院分区：
文献类型：
--
作者：
Alexopoulos, John A.;Guarne, Alba;Ortega, Joaquin
蛋白质降解是细菌生理学许多方面的重要过程。CLP蛋白水解酶在细菌中进行很大比例的蛋白质降解。这些酶组装在结合了蛋白酶ClpP和未折叠酶ClpA或ClpX的复合体中。ClpP寡聚为两个堆叠的七聚体环，包围着一个包含蛋白水解点的中央腔室。ClpX和CIPA组装成六角体环，将ClpP十四聚体的两个轴向表面结合在一起，形成桶状复合体。ClpP需要与ClpA或ClpX结合来展开蛋白质底物，并通过轴向孔将蛋白质底物穿入发生降解的内腔。受ATPase调控的门控机制存在于ClpP轴孔的入口处，并涉及ClpP原型的N-末端区域。这些门控基序位于十四聚体的轴向区域，但在大多数晶体结构中看不到它们。我们也缺乏关于ClpAP或ClpXP复合体的结构信息。因此，关于ClpP中的轴向门如何受ATPase调控的结构细节尚不清楚。在这里，我们回顾了我们目前对CIPA或ClpX在ClpP中诱导的构象变化的理解，这些变化打开了轴向门，增加了底物进入降解室的可及性。这些知识大部分来自最近与酰基二肽(ADEP)抗生素络合物中ClpP的晶体结构。这些小分子模拟了ClpA/ClpX与ClpP的相互作用，并激活了其蛋白酶活性，从而为了解该酶的门控机制提供了新的见解。(C)2012 Elsevier Inc.保留所有权利。
Proteolysis is an important process for many aspects of the bacterial physiology. Clp proteases carry out a large proportion of protein degradation in bacteria. These enzymes assemble in complexes that combine the protease ClpP and the unfoldase, ClpA or ClpX. ClpP oligomerizes as two stacked heptameric rings enclosing a central chamber containing the proteolytic sites. ClpX and CIpA assemble into hexameric rings that bind both axial surfaces of the ClpP tetradecamer forming a barrel-like complex. ClpP requires association with ClpA or ClpX to unfold and thread protein substrates through the axial pore into the inner chamber where degradation occurs. A gating mechanism regulated by the ATPase exists at the entry of the ClpP axial pore and involves the N-terminal regions of the ClpP protomers. These gating motifs are located at the axial regions of the tetradecamer but in most crystal structures they are not visible. We also lack structural information about the ClpAP or ClpXP complexes. Therefore, the structural details of how the axial gate in ClpP is regulated by the ATPases are unknown. Here, we review our current understanding of the conformational changes that CIpA or ClpX induce in ClpP to open the axial gate and increase substrate accessibility into the degradation chamber. Most of this knowledge comes from the recent crystal structures of ClpP in complex with acyldepsipeptides (ADEP) antibiotics. These small molecules are providing new insights into the gating mechanism of this protease because they imitate the interaction of ClpA/ClpX with ClpP and activate its protease activity. (C) 2012 Elsevier Inc. All rights reserved.