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Open AccessArticle

Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations

Institute of Biomechanics/School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
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Int. J. Mol. Sci. 2020, 21(19), 7064; https://doi.org/10.3390/ijms21197064
Received: 30 August 2020 / Revised: 20 September 2020 / Accepted: 23 September 2020 / Published: 25 September 2020
(This article belongs to the Special Issue Computer Simulation on Membrane Receptors and Lipid Bilayers)
The PSGL-1-actin cytoskeleton linker proteins ezrin/radixin/moesin (ERM), an adaptor between P-selectin glycoprotein ligand-1 (PSGL-1) and spleen tyrosine kinase (Syk), is a key player in PSGL-1 signal, which mediates the adhesion and recruitment of leukocytes to the activated endothelial cells in flow. Binding of PSGL-1 to ERM initials intracellular signaling through inducing phosphorylation of Syk, but effects of tensile force on unligation and phosphorylation site exposure of ERM bound with PSGL-1 remains unclear. To answer this question, we performed a series of so-called “ramp-clamp” steered molecular dynamics (SMD) simulations on the radixin protein FERM domain of ERM bound with intracellular juxtamembrane PSGL-1 peptide. The results showed that, the rupture force of complex pulled with constant velocity was over 250 pN, which prevented the complex from breaking in front of pull-induced exposure of phosphorylation site on immunoreceptor tyrosine activation motif (ITAM)-like motif of ERM; the stretched complex structure under constant tensile forces <100 pN maintained on a stable quasi-equilibrium state, showing a high mechano-stabilization of the clamped complex; and, in consistent with the force-induced allostery at clamped stage, increasing tensile force (<50 pN) would decrease the complex dissociation probability but facilitate the phosphorylation site exposure, suggesting a force-enhanced biophysical connectivity of PSGL-1 signaling. These force-enhanced characters in both phosphorylation and unligation of ERM bound with PSGL-1 should be mediated by a catch-slip bond transition mechanism, in which four residue interactions on binding site were involved. This study might provide a novel insight into the transmembrane PSGL-1 signal, its biophysical connectivity and molecular structural basis for cellular immune responses in mechano-microenvironment, and showed a rational SMD-based computer strategy for predicting structure-function relation of protein under loads. View Full-Text
Keywords: PSGL-1; ERM protein; Syk; ITAM-like motif; leukocyte; molecular dynamics simulations PSGL-1; ERM protein; Syk; ITAM-like motif; leukocyte; molecular dynamics simulations
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MDPI and ACS Style

Feng, J.; Zhang, Y.; Li, Q.; Fang, Y.; Wu, J. Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations. Int. J. Mol. Sci. 2020, 21, 7064. https://doi.org/10.3390/ijms21197064

AMA Style

Feng J, Zhang Y, Li Q, Fang Y, Wu J. Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations. International Journal of Molecular Sciences. 2020; 21(19):7064. https://doi.org/10.3390/ijms21197064

Chicago/Turabian Style

Feng, Jingjing; Zhang, Yan; Li, Quhuan; Fang, Ying; Wu, Jianhua. 2020. "Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations" Int. J. Mol. Sci. 21, no. 19: 7064. https://doi.org/10.3390/ijms21197064

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