Autoinhibition

Autoinhibition is a regulatory strategy in which a protein's own regions restrain its activity in the absence of a signal. Many enzymes and signaling proteins contain an autoinhibitory domain (AID) or a pseudosubstrate motif that binds to the active site or otherwise blocks substrate access, keeping the protein in a low-activity state until the constraint is relieved.

The inhibition is often intramolecular and can be relieved by conformational changes triggered by ligand binding, calcium/calmodulin, phosphorylation, or binding of regulatory subunits or partner proteins. Other routes include proteolytic cleavage to remove the inhibitory segment or allosteric rearrangements that reposition elements so the active site becomes accessible. In some cases, constitutive signaling results from mutations that disrupt the autoinhibitory interaction.

Examples include Src family kinases, which are held inactive by a C-terminal tail and regulatory domains and activated by relief of autoinhibition through phosphorylation and ligand binding; CaMKII, where the autoinhibitory segment blocks substrate access until Ca2+/calmodulin binds; and the catalytic subunits of PKA that are released from regulatory subunits when cAMP binds. Zymogens such as digestive proteases are activated by proteolytic removal of their inhibitory pro-domains.

Autoinhibition allows tight spatial and temporal control of activity and rapid response to signals. Dysregulation can contribute to disease, including constitutive kinase activity in cancer. Studying autoinhibition involves structural biology, mutational analysis, and biochemical assays to map inhibitory interfaces and their release mechanisms.