Rag A (RRAGA) Activators

Rag A, commonly referred to as RRAGA, is a member of the Rag GTPases family, which includes four proteins: Rag A/B and Rag C/D. These GTPases play a pivotal role in nutrient sensing, specifically amino acid sensing, and are intricately involved in the regulation of the mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway. mTORC1, a crucial regulator of cell growth and metabolism, is activated upon sensing sufficient amino acid levels, a process that involves the translocation of mTORC1 to the lysosomal surface, mediated by the Rag GTPases. In their active states, Rag A/B binds GTP while Rag C/D binds GDP, leading to mTORC1 activation.

RRAGA activators, in the context of the above, would be molecules that can promote the GTP-bound state of RRAGA or enhance its ability to interact with its partners in the pathway. Given the importance of amino acid sensing in this pathway, certain amino acids, notably leucine and arginine, have been found to play roles in the activation of the Rag GTPases and consequently mTORC1 signaling. Apart from amino acids, specific proteins and cellular components might influence the activation state of RRAGA. For instance, certain lysosomal proteins and vacuolar ATPases are implicated in sensing amino acid availability and modulating Rag GTPase activation. Additionally, protein complexes, such as GATOR1 and GATOR2, regulate the nucleotide-loading states of the Rag GTPases, with GATOR1 acting as a GTPase-activating protein for Rag A and B.