Autoinhibition of mixed lineage kinase 3 through its Src homology 3 domain.

IF 0.1 3区 文学 0 LITERARY REVIEWS CHICAGO REVIEW Pub Date : 2001-12-07 DOI:10.1074/jbc.M107176200
H Zhang, K A Gallo
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引用次数: 78

Abstract

Mixed lineage kinase 3 (MLK3) is a serine/threonine protein kinase that functions as a mitogen-activated protein kinase kinase kinase to activate the c-Jun NH(2)-terminal kinase pathway. MLK3 has also been implicated as an I kappa B kinase kinase in the activation of NF-kappa B. Amino-terminal to its catalytic domain, MLK3 contains a Src homology 3 (SH3) domain. SH3 domains harbor three highly conserved aromatic amino acids that are important for ligand binding. In this study, we mutated one of these corresponding residues within MLK3 to deliberately disrupt the function of its SH3 domain. This SH3-defective mutant of MLK3 exhibited increased catalytic activity compared with wild type MLK3 suggesting that the SH3 domain negatively regulates MLK3 activity. We report herein that the SH3 domain of MLK3 interacts with full-length MLK3, and we have mapped the site of interaction to a region between the zipper and the Cdc42/Rac interactive binding motif. Interestingly, the SH3-binding region contains not a proline-rich sequence but, rather, a single proline residue. Mutation of this sole proline abrogates SH3 binding and increases MLK3 catalytic activity. Taken together, these data demonstrate that MLK3 is autoinhibited through its SH3 domain. The critical proline residue in the SH3-binding site of MLK3 is conserved in the closely related family members, MLK1 and MLK2, suggesting a common autoinhibitory mechanism among these kinases. Our study has revealed the first example of SH3 domain-mediated autoinhibition of a serine/threonine kinase and provides insight into the regulation of the mixed lineage family of protein kinases.

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通过 Src 同源 3 结构域自动抑制混合系激酶 3。
混合血统激酶 3(MLK3)是一种丝氨酸/苏氨酸蛋白激酶,具有丝裂原活化蛋白激酶激酶的功能,可激活 c-Jun NH(2)-末端激酶通路。MLK3 在其催化结构域的氨基末端含有一个 Src 同源 3(SH3)结构域。SH3 结构域含有三个高度保守的芳香族氨基酸,对配体结合非常重要。在这项研究中,我们突变了 MLK3 中的一个相应残基,故意破坏其 SH3 结构域的功能。与野生型 MLK3 相比,这种 SH3 缺陷突变体 MLK3 的催化活性有所提高,这表明 SH3 结构域对 MLK3 的活性有负向调节作用。我们在本文中报告了 MLK3 的 SH3 结构域与全长 MLK3 的相互作用,并将相互作用的位点绘制到了拉链与 Cdc42/Rac 交互结合基序之间的区域。有趣的是,SH3 结合区不包含富含脯氨酸的序列,而只包含一个脯氨酸残基。突变这唯一的一个脯氨酸,可以消除 SH3 结合,提高 MLK3 的催化活性。综上所述,这些数据证明了 MLK3 是通过其 SH3 结构域进行自动抑制的。MLK3的SH3结合位点中的关键脯氨酸残基在密切相关的家族成员MLK1和MLK2中是保守的,这表明这些激酶之间存在共同的自抑机制。我们的研究首次揭示了由 SH3 结构域介导的丝氨酸/苏氨酸激酶的自身抑制作用,为我们深入了解蛋白激酶混系家族的调控机制提供了新的视角。
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CHICAGO REVIEW
CHICAGO REVIEW LITERARY REVIEWS-
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