A vital first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we solved crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of RAF1. Our structures revealed that RBD and CRD interact with each other to form one structural entity in which both RBD and CRD interact extensively with KRAS. Mutation at the KRAS-CRD interface resulted in a significant reduction in RAF1 activation despite only a modest decrease in binding affinity. Combining our structures and published data, we provide a model of RAS-RAF complexation at the membrane, and molecular insights into RAS-RAF interaction during the process of RAS-mediated RAF activation.

中文翻译：

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KRAS与RAF1 RAS结合域和富含半胱氨酸的域的相互作用提供了对RAS介导的RAF激活的见解

RAF活化的至关重要的第一步涉及与活性RAS结合，从而导致RAF募集至质膜。为了了解RAS-RAF相互作用的分子细节，我们解决了野生型和致癌突变体KRAS的晶体结构，该突变体与RAS结合域（RBD）和膜相互作用的富含半胱氨酸的域（CRD）结合而成， RAF1的末端调控区。我们的结构表明，RBD和CRD相互作用形成一种结构实体，其中RBD和CRD都与KRAS广泛相互作用。尽管结合亲和力仅适度降低，但KRAS-CRD界面的突变导致RAF1活化显着降低。结合我们的结构和公开的数据，我们提供了膜上RAS-RAF络合的模型，