Autoinhibitory

Autoinhibitory describes a regulatory mechanism in which a protein or enzyme suppresses its own activity through an intrinsic part of its structure. In this arrangement, a regulatory domain or segment interacts with the active site, substrate-binding site, or another functional interface to keep the molecule in an inactive or low-activity state until a signal relieves the inhibition.

Mechanisms of autoinhibition are diverse. They typically involve intramolecular interactions that block catalytic or binding surfaces, but can also be modulated by external factors such as phosphorylation, ligand binding, proteolytic cleavage, or association with partner proteins. Activation often requires a conformational change that disengages the autoinhibitory element, exposure of the catalytic site, or repositioning of regulatory domains. Autoinhibition can thus create switch-like behavior, provide a safeguard against spurious signaling, and enable spatial or temporal control of activity.

Notable examples include SHP2, a protein tyrosine phosphatase regulated by autoinhibitory interactions between its N-terminal SH2 domain and the catalytic domain; binding of phosphotyrosine-containing partners relieves inhibition and activates the enzyme. Src family kinases are also classically autoinhibited by a phosphorylated C-terminal tail that binds intramolecularly to SH2 and SH3 domains, with activation achieved upon tail dephosphorylation or engaging activators. Cyclin-dependent kinases use an activation loop and cyclin binding to overcome autoinhibition, while many proteases are synthesized as zymogens with propeptides that block the active site and are removed to activate them. In ion channels, inactivation gates or regulatory peptides can act as autoinhibitory elements that restrict pore opening.