Thromb Res. 2025 Apr 16;250:109320. doi: 10.1016/j.thromres.2025.109320. Online ahead of print.
ABSTRACT
The platelet αIIbβ3 integrin is the most abundant platelet receptor, orchestrating platelet adhesion, activation, and mechano-sensing during hemostasis and thrombosis. Disulfide bonds are the covalent links between the sulfur atoms of two cysteine residues and their role in the functioning of αIIbβ3 has been a topic of investigation for over two decades. The advent of differential cysteine alkylation using isotopic alkylators and mass spectrometry has led to the identification of multiple partially disulfide-bonded states of αIIbβ3 that are constitutively produced by megakaryocytes and reside in the platelet surface membrane, and an allosteric disulfide that is cleaved in the mature receptor to control function. One of the disulfide-bonded integrin states has reduced capacity due to particular clustering, internalisation, and recycling dynamics and lower avidity for fibrinogen, suggesting that other states may also have specific properties. Cleavage of an allosteric disulfide bond in the activated integrin uncouples the receptor from its ligand, and it is likely that other allosteric disulfides are yet to be identified. This review presents the current knowledge of the role of specific disulfide bonds in the regulation of αIIbβ3 integrin and perspectives on the future.
PMID:40300222 | DOI:10.1016/j.thromres.2025.109320