Prediction of Cancer-Associated Hotspot Mutations that Affect GPCR Oligomerization

Abstract

Numerous studies have reported that G-Protein Coupled Receptors (GPCRs) function not only as monomers but also as complexes including homo/hetero-dimers and higher-order oligomers. Many GPCRs exert different molecular functions by forming complexes with specific combinations of GPCR subtypes. In addition, some cases of GPCR oligomerization are reportedly associated with diseases. Despite the functional importance of GPCR oligomerization, the complete view of the GPCR-GPCR interactions has remained unknown. Hence, an accurate method to predict GPCR-GPCR prediction could accelerate the research of GPCRs. We recently developed a high performance method to predict interacting pairs for GPCR oligomerization, GPCR-GPCR Interaction Pair predictor (GGIP), by integrating the structure and sequence information of GPCRs [Nemoto et al. Proteins. 2016;84:1224-33].A recent study reported that somatic mutations in GPCR-encoding genes are frequently found in various types of cancer. Among the somatic mutations, hotspot mutations are defined as recurrent amino acid changes occurring in coding sequences. It has been revealed that many GPCRs have hotspot mutations in the same types of cancer tissues. However, most of the hotspot mutations have not been characterized yet, and their effects on the cancer pathways remain unknown. Some of the hotspot mutations may be related to cancers through modifying GPCR oligomerization, since they are considered to be present on the surface of transmembrane helices. Hence, we examined the predicted interacting pairs including the GPCRs with hotspot mutations. We will discuss the characteristics of these mutations and introduce several examples.