Biomolecular mimicry in the actin cytoskeleton: Mechanisms underlying the cytotoxicity of kabiramide C and related macrolides
Biomolecular mimicry in the actin cytoskeleton: Mechanisms underlying the cytotoxicity of kabiramide C and related macrolides
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DOI：
10.1073/pnas.2233339100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Marriott, G
中科院分区：
文献类型：
--
作者：
Tanaka, J;Yan, YL;Marriott, G
本研究的特点卡比胺C（KabC）和相关的大环内酯和肌动蛋白之间的相互作用，并建立其抑制肌动蛋白丝动力学和细胞毒性的机制。G-肌动蛋白-KabC复合物通过两步结合反应形成，并且非常稳定和长寿命。竞争结合研究表明，KabC与凝溶胶蛋白结构域1和CapG结合G-肌动蛋白上的相同位点。KabC还结合F-肌动蛋白内的原聚体，并导致（+）端的切断和加帽;这些研究表明，游离KabC和相关的大环素充当凝溶胶蛋白的仿生物。G-肌动蛋白-KabC复合物结合到生长中的细丝的（+）端，在那里它作为一种新的、不受调节的（+）端封端剂发挥作用，并且在大约10 -100 nM KabC处理的细胞中主要负责运动性和胞质分裂的抑制。KabC和相关的大环内酯是研究肌动蛋白丝（+）末端调节的有用探针，并可能导致治疗肌动蛋白细胞骨架疾病的新疗法。
This study characterizes the interactions between kabiramide C (KabC) and related macrolicles and actin and establishes the mechanisms that underlie their inhibition of actin filament dynamics and cytotoxicity. The G-actin-KabC complex is formed through a two-step binding reaction and is extremely stable and long-lived. Competition-binding studies show that KabC binds to the same site on G-actin as Gelsolin domain 1 and CapG. KabC also binds to protomers within F-actin and results in the severing and capping of the (+) end; these studies suggest that free KabC and related macrolicles act as biomimetics of Gelsolin. The G-actin-KabC complex binds to the(+)end of a growing filament, where it functions as a novel, unregulated, (+)-end capper and is largely responsible for the inhibition of motility and cytokinesis in approximate to10-100 nM KabC-treated cells. KabC and related macrolicles are useful probes to study the regulation of the actin filament (+) end and may lead to new therapies to treat diseases of the actin cytoskeleton.