Inside-out signaling during platelet activation triggers conformational changes in the platelet glycoprotein IIb/IIIa complex (integrin αIIbβ3, GPIIb/IIIa, ITGA2B:ITGB3) leading to the transition of αIIbβ3 (ITGA2B:ITGB3) from a low-affinity to a high-affinity state. This transition is essential for effective αIIbβ3 (ITGA2B:ITGB3) binding to the ligands such as fibrinogen and fibrin, which is converted from fibrinogen by thrombin (Dai A et al., 2015; reviewed in Janus-Bell E & Mangin PH 2023). Integrin αIIbβ3 interacts with ligands-containing Arg-Gly-Asp (RGD) or Ala--Gly-Asp (AGD) motifs in the presence of divalent metal ions (Springer TA et al., 2008; Coller BS 2015; Litvinov RI et al., 2016; Kononova O et al., 2017). The activation of αIIbβ3 not only promotes platelet aggregation but also influences the stability and architecture of the forming clot (Zhang Y et al., 2018; reviewed by Janus-Bell E & Mangin PH 2023). Fibrin in its polymeric form exhibits stronger and more stable interactions with αIIbβ3 than fibrinogen or fibrin monomers, with the stability order being fibrin polymer > fibrin monomer > fibrinogen (Litvinov RI et al., 2016; Höök P et al., 2017). The interaction between fibrin and αIIbβ3 occurs through multiple binding sites within the β-propeller domain of αIIbβ3, distinct from those used by fibrinogen (Podolnikova NP et al., 20014). Further, fibrinogen and αIIbβ3 (ITGA2B:ITGB3) promote association of phosphatidylserine (PS)-bearing activated platelets with factor XIII (FXIII), a transglutaminase, which stabilizes the clot by cross-linking fibrin fibers (Mattheij NJA 20016; Kotova YN et al., 2019). Fibrinogen binding to αIIbβ3 is thought to contribute to platelet aggregation, while the stronger interaction with fibrin stabilizes the thrombus (Savage B et al., 1992; Zafar H et al., 2017; Litvinov RI et al., 2016; Höök P et al., 2017).
This Reactome event shows binding of αIIbβ3 (ITGA2B:ITGB3) to the fibrin multimer.
