A histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1.

Complex chain reactions between many kinds of molecules regulate every process in the body. For example, the signaling molecule Ras helps the cell to grow and divide. However, abnormally high levels of Ras signals can cause cancer. Ras is activated by proteins called exchange factors. One of the families of Ras exchange factors – RasGRP – plays important roles in immune and bleeding disorders, and certain cancers. In 2013, researchers studied the structure of one of these exchange factors, called RasGRP1, while it was inactivated. Inactive RasGRP proteins have a ‘closed’ structure, which must ‘open up’ when they are activated. Vercoulen, Kondo, Iwig et al. – who include several of the researchers involved in the 2013 study – have now investigated the regulation of various RasGRP family members. The protein structures of the active forms of two family members were determined and compared with the structure of inactive RasGRP1. In parallel, Vercoulen et al. analyzed how genetic mutations that alter some of the amino acids that make up RasGRP1 affect Ras signaling in cells. This revealed that a particular amino acid, histidine 212, plays a key role in activating RasGRP1. Histidines can be in a positively charged or neutral form depending on other surrounding amino acids and on the acidity of the cell’s interior. The interiors of cells that receive an external signal often decrease in acidity, and cancer cells tend to have less acidic interiors than normal cells. Vercoulen et al. reveal that a change in the charge on histidine 212 from positive to neutral opens up the RasGRP1 protein. Histidine 212 therefore acts as an acidity sensor that activates RasGRP1 when the inside of the cell becomes less acidic as external signals are received. Since RasGRP proteins play important roles in many diseases, understanding how cell acidity regulates RasGRPs has wide medical relevance. In the future, the protein structures of the RasGRP family members and the method developed in this study could be used to explore how they contribute to disease.