Functional consequences of thiol isomerase-mediated disulfide bond modifications. Thiol isomerases are secreted from platelets and endothelium following cell activation and mediate modifications of functional disulfide bonds in multiple substrates. Several categories of modifications are observed. (1) Exposure of binding sites in adhesion proteins. Cleavage of disulfide bonds can reveal cryptic binding sites such as RGD sequences (shown in blue) enabling a nonbinding adhesion protein (red) to adhere to binding partners on the cell surface (green). Thrombospondin is an adhesion protein that is modified in this manner.⁵³  (2) Activation of enzyme function. Functional disulfide bond cleavage could also expose an encrypted active site within an enzyme or modify its conformation, converting the enzyme to a more active conformation. Conversely, formation of a disulfide bond could activate an enzyme or coenzyme (eg, tissue factor).^65,66,93  (3) Receptor activation. Disulfide bond shuffling could contribute to the formation or stabilization of the active conformation of cell surface receptors (eg, α_IIbβ₃).^47,75  (4) Release from binding protein. Cleavage of a disulfide bond could release a protein from its binding partner, thereby activating the protein (eg, TGF-β).⁹⁴