Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina.
Adv Cancer Res. 2024;164:69-91. doi: 10.1016/bs.acr.2024.04.009. Epub 2024 May 14.
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 激酶，包括 ARAF、BRAF 和 CRAF，是 RAS GTPases 的直接效应物，对于通过 RAS-MAPK 途径进行信号转导至关重要。BRAF 中的驱动突变在人类癌症中很常见，而 BRAF 和 CRAF 的种系突变会导致 RAS 病发展综合征。然而，目前仍然缺乏针对 RAF 功能的有效药物，部分原因是 RAF 激活循环的复杂性。因此，需要更好地了解 RAF 调节机制，以确定针对其在疾病中功能的新方法。这一难题的关键部分是 RAF 锌指，通常称为富含半胱氨酸的结构域（CRD）。CRD 是一个脂质和蛋白质结合域，在 RAF 激活循环中发挥着复杂且相反的作用。首先，它通过与质膜中的磷脂酰丝氨酸（PS）结合以及与 RAS 直接接触，在 RAF 激活过程中支持 RAS-RAF 相互作用。相反，在静止状态下，CRD 也在维持 RAF 处于封闭的、自动抑制状态中发挥着关键作用。然而，这些活性之间的相互作用及其对 RAF 激活的相对重要性尚未得到很好的理解。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，并确定了 BRAF CRD 与 CRAF 的 CRD 之间的功能差异。本章深入探讨了 CRD 在 RAF 调节中的作用，以及它们如何为靶向 RAF 功能的新方法提供信息。
