The RAF cysteine-rich domain: Structure, function, and role in disease.

Advances in cancer research Pub Date : 2024-01-01 Epub Date: 2024-05-14 DOI:10.1016/bs.acr.2024.04.009
Russell Spencer-Smith
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Abstract

RAF kinases, consisting of ARAF, BRAF and CRAF, are direct effectors of RAS GTPases and critical for signal transduction through the RAS-MAPK pathway. Driver mutations in BRAF are commonplace in human cancer, while germline mutations in BRAF and CRAF cause RASopathy development syndromes. However, there remains a lack of effective drugs that target RAF function, which is partially due to the complexity of the RAF activation cycle. Therefore, greater understanding of RAF regulation is required to identify new approaches that target its function in disease. A key piece of this puzzle is the RAF zinc finger, often referred to as the cysteine-rich domain (CRD). The CRD is a lipid and protein binding domain which plays complex and opposing roles in the RAF activation cycle. Firstly, it supports the RAS-RAF interaction during RAF activation by binding to phosphatidylserine (PS) in the plasma membrane and by making direct RAS contacts. Conversely, under quiescent conditions the CRD also plays a critical role in maintaining RAF in a closed, autoinhibited state. However, the interplay between these activities and their relative importance for RAF activation were not well understood. Recent structural and biochemical studies have contributed greatly to our understanding of these roles and identified functional differences between BRAF CRD and that of CRAF. This chapter provides an in-depth review of the CRDs roles in RAF regulation and how they may inform novel approaches to target RAF function.

RAF 富半胱氨酸结构域:结构、功能和在疾病中的作用
由 ARAF、BRAF 和 CRAF 组成的 RAF 激酶是 RAS GTP 酶的直接效应器,对于通过 RAS-MAPK 途径进行信号转导至关重要。BRAF 的驱动突变在人类癌症中很常见,而 BRAF 和 CRAF 的种系突变则会导致 RAS 病发展综合征。然而,目前仍缺乏针对 RAF 功能的有效药物,部分原因在于 RAF 激活循环的复杂性。因此,需要进一步了解 RAF 的调控,以确定针对其在疾病中的功能的新方法。RAF锌指(通常称为富半胱氨酸结构域(CRD))是这一难题的关键部分。CRD是一个脂质和蛋白质结合结构域,在RAF活化循环中发挥着复杂而相反的作用。首先,在 RAF 激活过程中,它通过与质膜上的磷脂酰丝氨酸(PS)结合以及与 RAS 直接接触来支持 RAS-RAF 相互作用。相反,在静止状态下,CRD 在使 RAF 保持封闭、自抑制状态方面也起着关键作用。然而,人们对这些活性之间的相互作用及其对 RAF 激活的相对重要性还不甚了解。最近的结构和生化研究极大地促进了我们对这些作用的理解,并发现了 BRAF CRD 与 CRAF CRD 在功能上的差异。本章深入评述了 CRD 在 RAF 调控中的作用,以及它们如何为靶向 RAF 功能的新方法提供信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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