Serpin

Serpins are a superfamily of proteins that primarily function as serine protease inhibitors. Although called serine protease inhibitors, many serpins inhibit a broad range of proteases, and some have evolved non-inhibitory roles. The family is widely distributed across life, with vertebrates encoding large serpins for extracellular proteolysis regulation, immune function, hemostasis, and development. Serpins can be secreted into blood or interstitial fluids, or act intracellularly.

A defining feature is a structurally conserved fold of about eight to nine beta-sheets and three alpha-helices, stabilized by a reactive center loop (RCL) at the C-terminus. Inhibition occurs via a suicide mechanism: the target protease cleaves the RCL, and the serpin undergoes a large conformational change that traps the protease in a covalent complex, irreversibly inactivating both. The specificity is determined mainly by the amino acid sequence of the RCL near the cleavage site.

Physiological roles include regulation of coagulation, inflammation, complement, fibrinolysis, and tissue remodeling. Notable serpins include antithrombin III (SERPINC1), which inhibits thrombin and factor Xa; alpha-1 antitrypsin (SERPINA1), a neutrophil elastase inhibitor; C1 esterase inhibitor (SERPING1), which controls the complement pathway; plasminogen activator inhibitor-1 (SERPINE1), which modulates fibrinolysis. Some serpins are intracellular and protect cells from proteolysis, and a few have non-inhibitory functions such as acting as tumor suppressors.

Dysfunction can cause serpinopathies, often due to misfolding and polymerization. Examples include alpha-1 antitrypsin deficiency, which predisposes to lung and liver disease, and neuroserpin-related encephalopathies. The serpin family is the subject of ongoing research for therapeutic modulation of proteolysis in diverse diseases.