Blood: The Structural Foundation of PAR4 Activation and Its Role in VTE

Protease activation receptor 4 (PAR4) mediates the continuous signalconductofing of clotting enzymes in platelets, which is necessary to stabilizeblood clotsPAR4 is activated by protein hydrolysis at the end of N to expose the binding ligandThe structural basis of PAR4 activation and the location of its ligand binding site (LBS) have not been specifiedthrough hydrogen/niobium exchange (H/D exchange), computational models, and signal studies, Han et alidentified the molecular mechanisms of PAR4 activation by binding ligand-mediatedH/D switching clear LBS consists of cross-membrane domains 3 (TM3) and TM7The non-biased calculation model further predicts the interaction between Gly48 from the bondage ligand and Thr153 from LBSThe Thr153 mutation significantly reduces PAR4 signal conductionH/D switching and modeling also showed that the outer ring of the cell 3 (ECL3) acts as a goalkeeper for the interaction between the binding ligand and the LBSThrough naturally occurring variants (P310L, rs2227376) and two experimental mutations (S311A and P312L), the rigidity provided by proline in ECL3 is essential for PAR4 activationfinally, the researchers examined the role of polymorphism in vein thromboembolism (VTE) at 310 (rs2227376) and found that individuals carrying the PAR4 Leu310 allele had a 15% lower relative risk of VTE than those carrying the Pro310 allele (advantage ratio of 0.85, 95% CI: 0.77-0.94)in general, this study found the structural basis of PAR4 activation and revealed the previously undiscovered effects of PAR4 in VTE