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Publication Abstract from PubMed

The inhibition of physiological activation pathways of the platelet adhesion receptor integrin alphaIIbbeta3 may fail to prevent fatal thrombosis, suggesting that the receptor is at risk of activation by yet an unidentified pathway. Here, we report the discovery and characterization of a structural motif that safeguards the receptor by selectively destabilizing its inactive state. At the extracellular membrane border, an overpacked alphaIIb(W968)-beta3(I693) contact prevents alphaIIb(Gly972) from optimally assembling the alphaIIbbeta3 transmembrane complex, which maintains the inactive state. This destabilization of approximately 1.0 kcal/mol could be mitigated by hydrodynamic forces but not physiological agonists, thereby identifying hydrodynamic forces as pathological activation stimulus. As reproductive life spans are not generally limited by cardiovascular disease, it appears that the evolution of the safeguard was driven by fatal, hydrodynamic force-mediated integrin alphaIIbbeta3 activation in the healthy cardiovascular system. The triggering of the safeguard solely by pathological stimuli achieves an effective increase of the free energy barrier between inactive and active receptor states without incurring an increased risk of bleeding. Thus, integrin alphaIIbbeta3 has evolved an effective way to protect receptor functional states that indicates the availability of a mechanical activation pathway when hydrodynamic forces exceed physiological margins.

Insight Into Pathological Integrin alphaIIbbeta3 Activation From Safeguarding The Inactive State.,Situ AJ, Kim J, An W, Kim C, Ulmer TS J Mol Biol. 2021 Apr 2;433(7):166832. doi: 10.1016/j.jmb.2021.166832. Epub 2021 , Feb 2. PMID:33539882^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.