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首页> 外文期刊>Journal of Molecular Biology >The Molecular Motor F-ATP Synthase Is Targeted by the Tumoricidal Protein HAMLET
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The Molecular Motor F-ATP Synthase Is Targeted by the Tumoricidal Protein HAMLET

机译：分子运动F-ATP合酶是由杀肿瘤蛋白HAMLET靶向的。

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HAMLET (human alpha-lactalbumin made lethal to tumor cells) interacts with multiple tumor cell compartments, affecting cell morphology, metabolism, proteasome function, chromatin structure and viability. This study investigated if these diverse effects of HAMLET might be caused, in part, by a direct effect on the ATP synthase and a resulting reduction in cellular ATP levels. A dose-dependent reduction in cellular ATP levels was detected in A549 lung carcinoma cells, and by confocal microscopy, co-localization of HAMLET with the nucleotide-binding subunits alpha (non-catalytic) and beta (catalytic) of the energy converting F1F0 ATP synthase was detected. As shown by fluorescence correlation spectroscopy, HAMLET binds to the F-1 domain of the F1F0 ATP synthase with a dissociation constant (K-D) of 20.5 mu M. Increasing concentrations of the tumoricidal protein HAMLET added to the enzymatically active alpha(3)beta(3)gamma complex of the F-ATP synthase lowered its ATPase activity, demonstrating that HAMLET binding to the F-ATP synthase effects the catalysis of this molecular motor. Single-molecule analysis was applied to study HAMLET-alpha(3)beta(3)gamma complex interaction. Whereas the alpha(3)beta(3)gamma complex of the F-ATP synthase rotated in a counterclockwise direction with a mean rotational rate of 3.8 +/- 0.7 s(-1), no rotation could be observed in the presence of bound HAMLET. Our findings suggest that direct effects of HAMLET on the F-ATP synthase may inhibit ATP-dependent cellular processes. (C) 2015 Elsevier Ltd. All rights reserved.
机译：HAMLET（对肿瘤细胞具有致死性的人α-乳清蛋白）与多个肿瘤细胞区室相互作用，影响细胞形态，代谢，蛋白酶体功能，染色质结构和活力。这项研究调查了HAMLET的这些不同影响是否可能部分是由于对ATP合酶的直接影响以及由此导致的细胞ATP水平降低。在A549肺癌细胞中检测到剂量依赖性的细胞ATP水平降低，并且通过共聚焦显微镜检查，HAMLET与能量转换F1F0 ATP的核苷酸结合亚基α（非催化）和β（催化）共定位检测到合酶。如荧光相关光谱所示，HAMLET以20.5μM的解离常数（KD）与F1F0 ATP合酶的F-1结构域结合。增加浓度的杀菌蛋白HAMLET添加到酶促活性α（3）beta（ 3）F-ATP合酶的γ复合物降低了其ATP酶活性，表明HAMLET与F-ATP合酶的结合影响了该分子马达的催化作用。单分子分析用于研究HAMLET-alpha（3）beta（3）gamma复杂相互作用。尽管F-ATP合酶的alpha（3）beta（3）gamma络合物以逆时针方向旋转，平均旋转速率为3.8 +/- 0.7 s（-1），但在存在结合的情况下无法观察到旋转村庄。我们的发现表明，HAMLET对F-ATP合酶的直接作用可能会抑制ATP依赖的细胞过程。 （C）2015 Elsevier Ltd.保留所有权利。

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