Steered Molecular Dynamics Of PSGL-1/FERM Complex

Leukocyte migration into inflammatory lesions is tightly regulated by adhesion receptors and mediators of inflammation.PSGL-1(P-selectin glycorpotein ligand 1)interactions with endothelial selectins play a critical role in initiating the leukocyte adhesion cascade by mediating leukocyte tethering and rolling along inflamed vascular endothelium.In the process of leukocyte tethering and rolling,PSGL-1 engagement by endothelial selectins triggers a series of intracellular signals,including Syk(spleen tyrosine kinase)recruitment and activation.Once activated,Syk transmits signals to downstream molecules,leading to integrin-dependent leukocyte slow rolling,which promotes leukocyte recruitment into tissues.PSGL-1 cytoplasmic domain is essential to leukocyte slow rolling.Ezrin/radixin/moesin(ERM)proteins serve as adaptor molecules between PSGL-1 and Syk,which interacts with ITAM-like motif on ERM proteins and plays an important role in integrin activation and leukocyte slow rolling.Crystal structure analysis of the radixin FERM domain complexed with adhesion molecule PSGL-1 reveals that ITAM-like motif locates in FERM domain and contains phosphotyrosine-binding sites(Y191 and Y205),which can recruit and activate Syk.Howerer,crystal structure analysis shows that large space steric hindrance exists around ITAM-like motif and phosphotyrosine-binding sites(Y191 and Y205),which could hamper its phosphorylation and combination with Syk.In this paper,Steered Molecular Dynamics(SMD)was used to simulate the interaction of PSGL-1 juxtamembrane peptide with the radixin FERM domain in mechanical environment.Both conformational analysis and solvent accessible surface(SASA)showed that mechanical signal transducts through the PSGL-1 cytoplasmic region,mediating the exposition of ITAM-like motif and phosphotyrosine-binding site Y205,expect for the phosphotyrosine-binding site Y191.The results of this study revealed for the first time a mechanical signal pathway from PSGL-1 intracellular domain to Syk and expounds the structural basis of PSGL-1/ERM/Syk interaction at the atomic level.