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Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization.
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2020-01-27 , DOI: 10.1038/s41594-019-0365-0
Nicholas P D Liau 1 , Timothy J Wendorff 1 , John G Quinn 2 , Micah Steffek 2 , Wilson Phung 3 , Peter Liu 3 , Jia Tang 3 , Flaviyan J Irudayanathan 4 , Saeed Izadi 4 , Andrey S Shaw 5 , Shiva Malek 6 , Sarah G Hymowitz 1 , Jawahar Sudhamsu 1
Affiliation  

The RAS-RAF-MEK-ERK signaling axis is frequently activated in human cancers. Physiological concentrations of ATP prevent formation of RAF kinase-domain (RAFKD) dimers that are critical for activity. Here we present a 2.9-Å-resolution crystal structure of human BRAFKD in complex with MEK and the ATP analog AMP-PCP, revealing interactions between BRAF and ATP that induce an inactive, monomeric conformation of BRAFKD. We also determine how 14-3-3 relieves the negative regulatory effect of ATP through a 2.5-Å-resolution crystal structure of the BRAFKD-14-3-3 complex, in which dimeric 14-3-3 enforces a dimeric BRAFKD assembly to increase BRAF activity. Our data suggest that most oncogenic BRAF mutations alter interactions with ATP and counteract the negative effects of ATP binding by lowering the threshold for RAF dimerization and pathway activation. Our study establishes a framework for rationalizing oncogenic BRAF mutations and provides new avenues for improved RAF-inhibitor discovery.

中文翻译:

ATP 对 RAF 激酶活性的负调节被 14-3-3 诱导的二聚化克服。

RAS-RAF-MEK-ERK 信号轴在人类癌症中经常被激活。ATP 的生理浓度可防止对活性至关重要的 RAF 激酶结构域 (RAFKD) 二聚体的形成。在这里,我们展示了与 MEK 和 ATP 类似物 AMP-PCP 复合的人 BRAFKD 的 2.9-Å 分辨率晶体结构,揭示了 BRAF 和 ATP 之间的相互作用,从而诱导了 BRAFKD 的非活性单体构象。我们还确定了 14-3-3 如何通过 BRAFKD-14-3-3 复合物的 2.5-Å 分辨率晶体结构减轻 ATP 的负调节作用,其中二聚体 14-3-3 强制二聚体 BRAFKD 组装增加 BRAF 活动。我们的数据表明,大多数致癌 BRAF 突变改变了与 ATP 的相互作用,并通过降低 RAF 二聚化和通路激活的阈值来抵消 ATP 结合的负面影响。
更新日期:2020-01-27
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