G-proteins | Small GTPases

Ras superfamily small guanosine triphosphatases (GTPases) (20–25 kDa) are a large class of guanine nucleotide-binding proteins involved in the regulation of numerous signaling pathways and cellular processes in eukaryotic cells. The Ras oncoproteins are the founding members, with over 150 mammalian members now identified and functionally related orthologs found in invertebrates and plants. GTPases operate by a conserved mechanism of guanosine triphosphate (GTP) binding and hydrolysis that controls the activation state of the protein. The small GTPases are monomeric, distinguishing them from the heterotrimeric G proteins that are comprised of three separate subunits, α, β, and γ. Similar to the Gα subunits, small GTPases bind GTP with high affinity and catalyze the hydrolysis of the covalent bond between the two terminal GTP phosphate groups, producing protein-bound guanosine diphosphate (GDP) and a solvent-free phosphate. The cleavage of this bond releases energy that changes the conformation of the small GTPase to an inactive GDP-bound structure. In the presence of specific regulatory proteins, an intrinsic GDP/GTP exchange activity allows the reformation of the active GTP-bound conformation, which then interacts with one or more effector targets to promote a specific cellular response. This two-state structural change is fundamental for small GTPase biological function as a regulated binary switch.