RAF 家族激酶的调控:近期结构和生化研究的新发现。

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Russell Spencer-Smith, Deborah K Morrison
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引用次数: 0

摘要

RAF激酶是通过RAS-RAF-MEK-ERK途径进行信号转导所必需的,其活性在人类癌症和RAS病发育综合征中经常被上调。由于 RAF 的活化过程复杂,开发有效针对 RAF 功能的药物一直是一项具有挑战性的工作,这凸显了对 RAF 调控进行更详细了解的必要性。本综述将重点介绍最近的结构和生化研究,这些研究提供了 RAF 调控周期的 "快照",揭示了自抑制 BRAF 单体、活性 BRAF 和 CRAF 同源二聚体以及含有 CRAF 或 BRAFV600E 的 HSP90/CDC37 合子复合物的结构。此外,我们还将介绍有关 BRAF 如何在其调控状态之间转换的深入研究,并探讨各种 BRAF 结构域和 14-3-3 二聚体在维持 BRAF 作为自抑制单体和促进其向活性二聚体转换方面所起的作用。我们还将讨论 HSP90/CDC37 合子复合物在稳定 CRAF 和某些致癌 BRAF 突变体蛋白水平方面的功能,以及作为 PP5 蛋白磷酸酶介导的 RAF 去磷酸化平台的功能。最后,我们将讨论在 BRAF 和 CRAF 之间观察到的调控差异,以及这些差异如何影响 BRAF 和 CRAF 作为人类疾病驱动因素的功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Regulation of RAF family kinases: new insights from recent structural and biochemical studies.

The RAF kinases are required for signal transduction through the RAS-RAF-MEK-ERK pathway, and their activity is frequently up-regulated in human cancer and the RASopathy developmental syndromes. Due to their complex activation process, developing drugs that effectively target RAF function has been a challenging endeavor, highlighting the need for a more detailed understanding of RAF regulation. This review will focus on recent structural and biochemical studies that have provided 'snapshots' into the RAF regulatory cycle, revealing structures of the autoinhibited BRAF monomer, active BRAF and CRAF homodimers, as well as HSP90/CDC37 chaperone complexes containing CRAF or BRAFV600E. In addition, we will describe the insights obtained regarding how BRAF transitions between its regulatory states and examine the roles that various BRAF domains and 14-3-3 dimers play in both maintaining BRAF as an autoinhibited monomer and in facilitating its transition to an active dimer. We will also address the function of the HSP90/CDC37 chaperone complex in stabilizing the protein levels of CRAF and certain oncogenic BRAF mutants, and in serving as a platform for RAF dephosphorylation mediated by the PP5 protein phosphatase. Finally, we will discuss the regulatory differences observed between BRAF and CRAF and how these differences impact the function of BRAF and CRAF as drivers of human disease.

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来源期刊
Biochemical Society transactions
Biochemical Society transactions 生物-生化与分子生物学
CiteScore
7.80
自引率
0.00%
发文量
351
审稿时长
3-6 weeks
期刊介绍: Biochemical Society Transactions is the reviews journal of the Biochemical Society. Publishing concise reviews written by experts in the field, providing a timely snapshot of the latest developments across all areas of the molecular and cellular biosciences. Elevating our authors’ ideas and expertise, each review includes a perspectives section where authors offer comment on the latest advances, a glimpse of future challenges and highlighting the importance of associated research areas in far broader contexts.
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