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
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
International journal of molecular sciences - 21(2020), 19 vom: 25. Sept. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Feng, Jingjing [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.03.2021 Date Revised 02.03.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms21197064 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM315633816 |
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| 100 | 1 | |a Feng, Jingjing |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1 |b A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ERM protein | |
| 650 | 4 | |a ITAM-like motif | |
| 650 | 4 | |a PSGL-1 | |
| 650 | 4 | |a Syk | |
| 650 | 4 | |a leukocyte | |
| 650 | 4 | |a molecular dynamics simulations | |
| 650 | 7 | |a Cytoskeletal Proteins |2 NLM | |
| 650 | 7 | |a Membrane Glycoproteins |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a P-selectin ligand protein |2 NLM | |
| 650 | 7 | |a radixin |2 NLM | |
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| 700 | 1 | |a Zhang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Quhuan |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jianhua |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ijms21197064 |3 Volltext |
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