The platelet integrin alpha(IIb)beta(3) has an endogenous thiol isomerase activity

Integrins are cysteine-rich heterodimeric cell-surface adhesion molecules t hat alter their affinity for ligands in response to cellular activation. Th e molecular mechanisms involved in this activation of integrins are not und erstood. Treatment with the thiol-reducing agent, dithiothreitol, can induc e an activation-like state in many integrins suggesting that cysteine-cyste ine dithiol bonds are important for the receptor's tertiary structure and m ay be involved in activation-induced conformational changes. Here we demons trate that the platelet-specific integrin, alpha (IIb)beta (3), contains an endogenous thiol isomerase activity, predicted from the presence of the te trapeptide motif, CXXC, in each of the cysteine-rich repeats of the beta (3 ) polypeptide. This motif comprises the active site in enzymes involved in disulfide exchange reactions, including protein-disulfide isomerase (EC 5.3 .4.1) and thioredoxin. Intrinsic thiol isomerase activity is also observed in the related integrin, alpha (v)beta (3), which shares a common beta -sub unit. Thiol isomerase activity within alpha (IIb)beta (3) is time dependent and saturable, and is inhibited by the protein-disulfide isomerase inhibit or, bacitracin. Furthermore, this activity is calcium-sensitive and is regu lated in the EDTA-stabilized conformation of the integrin. This novel demon stration of an enzymatic activity associated with an integrin subunit sugge sts that altered thiol bonding within the integrin or its substrates may be locally modified during alpha (IIb)beta (3) activation.