GTPases and their Regulation

Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒  small G-proteins consisting of a single domain and large multi-domain G-proteins.

Large G-proteins, also known as heterotrimeric G-proteins, consist of three subunits —α, β, and γ. The α subunit has a conserved domain that interacts with G-protein-coupled receptors to mediate transmembrane signaling

Small G-proteins are a single subunit and signal throughout the cell in a variety of pathways. They are divided into five subfamilies based on sequence and function ‒ Ras, Rho, Rab, Ran, and Arf. Mutations in the Ras subfamily lead to the formation of cancerous tumors in the lungs, colon, and pancreas. The Rho subfamily regulates actin reorganization and microtubule cytoskeleton dynamics. The Rab subfamily, the largest small G-protein family, regulates vesicle transport and membrane trafficking in secretory and endocytic pathways.  The Ran subfamily regulates nucleocytoplasmic transport of RNA and proteins through the nuclear pore and mitotic spindle assembly and function. The Arf subfamily is involved in vesicle transport and membrane trafficking.

G-proteins are regulated by GTP/GDP binding and have intrinsic GTPase activity, meaning they can hydrolyze GTP to GDP.  When GTP is bound, the G-protein is in the “ON” state, that is the protein will promote signaling cascades in the cell.  When GDP is bound, it is in the “OFF” state, causing the signaling to stop. Regulation of G-protein activation further regulated by guanine nucleotide exchange factors (GEFs), which assist in GDP dissociation, and GTPase activating proteins (GAPs) that stimulate GTP hydrolysis. Additionally, guanine dissociation inhibitors (GDIs) can bind to small GTPases and regulate their location in the membrane or cytoplasm.