Chemical or enzymic reduction/oxidation of integrin cysteine residues (e.g. by reducing agents and protein disulphide isomerase) may be a mechanism for regulating integrin function. It has also been proposed that unique cysteine residues in the integrin β3 subunit are involved in the regulation of αIIbβ3. In the present study, we studied systematically the role of disulphide bonds in β3 on the ligand-binding function of αIIbβ3 by mutating individual cysteine residues of β3 to serine. We found that the disulphide bonds that are critical for αIIbβ3 regulation are clustered within the EGF (epidermal growth factor) domains. Interestingly, disrupting only a single disulphide bond in the EGF domains was enough to activate αIIbβ3 fully. In contrast, only two (of 13) disulphide bonds tested outside the EGF domains activated αIIbβ3. These results suggest that the disulphide bonds in the EGF domains should be intact to keep αIIbβ3 in an inactive state, and that there is no unique cysteine residue in the EGF domain critical for regulating the receptor. The cysteine residues in the EGF domains are potential targets for chemical or enzymic reduction.
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