Abstract
Protein disulfide isomerase (PDI), secreted by platelets and endothelial cells on vascular injury, is required for thrombus formation. Using PDI variants that form mixed disulfide complexes with their substrates, we identify by kinetic trapping multiple substrate proteins, including vitronectin. Plasma vitronectin does not bind to αvβ3 or αIIbβ3 integrins on endothelial cells and platelets. The released PDI reduces disulfide bonds on plasma vitronectin, enabling vitronectin to bind to αVβ3 and αIIbβ3. In vivo studies of thrombus generation in mice demonstrate that vitronectin rapidly accumulates on the endothelium and the platelet thrombus following injury. This process requires PDI activity and promotes platelet accumulation and fibrin generation. We hypothesize that under physiologic conditions in the absence of secreted PDI, thrombus formation is suppressed and maintains a quiescent, patent vasculature. The release of PDI during vascular injury may serve as a regulatory switch that allows activation of proteins, among them vitronectin, critical for thrombus formation.
Highlights
Protein disulfide isomerase (PDI), secreted by platelets and endothelial cells on vascular injury, is required for thrombus formation
Cell activation and receptor conformational transitions are important mechanisms for rapidly transforming a quiescent system into an active system, as characterized by the activation of the blood coagulation cascade and fibrin generation, endothelial cell activation and degranulation and platelet thrombus formation[1], but we have recently determined that protein disulfide isomerase (PDI) and several additional thiol isomerases may play an important role in maintaining the patency of the circulatory system
PDI, a prototype of a family of thiol isomerases with common thioredoxin-like domains and active sites characterized by the sequence CXXC, is an oxidoreductase involved in the formation of protein disulfide bonds during protein synthesis
Summary
Protein disulfide isomerase (PDI), secreted by platelets and endothelial cells on vascular injury, is required for thrombus formation. The release of PDI from the stimulated endothelium and bound platelets activates proteins, including vitronectin, critical for thrombus formation through modification of functional disulfide bonds[11].
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