Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer with rising cases in recent years. Extensive research has identified various cancer driver proteins associated with different subtypes of RCC. Most RCC drivers are encoded by tumor suppressor genes and exhibit enrichment in functional categories such as protein degradation, chromatin remodeling, and transcription. To further our understanding of RCC, we utilized powerful deep-learning methods based on AlphaFold to predict protein-protein interactions (PPIs) involving RCC drivers. We predicted high-confidence complexes formed by various RCC drivers, including TCEB1, KMT2C/D and KDM6A of the COMPASS-related complexes, TSC1 of the MTOR pathway, and TRRAP. These predictions provide valuable structural insights into the interaction interfaces, some of which are promising targets for cancer drug design, such as the NRF2-MAFK interface. Cancer somatic missense mutations from large datasets of genome sequencing of RCCs were mapped to the interfaces of predicted and experimental structures of PPIs involving RCC drivers, and their effects on the binding affinity were evaluated. We observed more than 100 cancer somatic mutations affecting the binding affinity of complexes formed by key RCC drivers such as VHL and TCEB1. These findings emphasize the importance of these mutations in RCC pathogenesis and potentially offer new avenues for targeted therapies.