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.
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.
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双相力调节磷酸化位点暴露以及与 PSGL-1 结合的 ERM 的解开：通过引导分子动力学模拟对 PSGL-1 信号传导的新见解
DOI：
10.3390/ijms21197064
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发表时间：
2020-09-25
影响因子：
5.6
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Feng J;Zhang Y;Li Q;Fang Y;Wu J
PSGL - 1 - 肌动蛋白细胞骨架连接蛋白埃兹蛋白/根蛋白/膜突蛋白（ERM）是P - 选择素糖蛋白配体 - 1（PSGL - 1）和脾酪氨酸激酶（Syk）之间的衔接蛋白，是PSGL - 1信号传导中的关键因子，它在血流中调节白细胞与活化内皮细胞的黏附和募集。PSGL - 1与ERM结合通过诱导Syk磷酸化启动细胞内信号传导，但张力对与PSGL - 1结合的ERM的去结合以及磷酸化位点暴露的影响仍不清楚。为了回答这个问题，我们对与细胞内近膜PSGL - 1肽段结合的ERM的根蛋白FERM结构域进行了一系列所谓的“斜坡 - 钳制”导向分子动力学（SMD）模拟。结果表明，以恒定速度牵拉复合物的断裂力超过250皮牛，这防止了复合物在牵拉诱导ERM的免疫受体酪氨酸激活基序（ITAM）样基序上的磷酸化位点暴露之前断裂；在恒定张力<100皮牛下拉伸的复合物结构保持在稳定的准平衡状态，显示出被钳制复合物的高度机械稳定性；并且，与钳制阶段的力诱导变构一致，增加张力（<50皮牛）会降低复合物解离概率但促进磷酸化位点暴露，表明PSGL - 1信号传导的力增强生物物理连接性。与PSGL - 1结合的ERM在磷酸化和去结合方面的这些力增强特性应是由一种“捕获 - 滑动键”转换机制介导的，其中涉及结合位点上的四个残基相互作用。这项研究可能为跨膜PSGL - 1信号、其生物物理连接性以及机械微环境中细胞免疫反应的分子结构基础提供新的见解，并展示了一种基于SMD的合理计算机策略，用于预测负载下蛋白质的结构 - 功能关系。
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.
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影响因子：
4.3
作者：
Borsig L
通讯作者：
Borsig L
DOI：
10.1126/stke.3772007re2
发表时间：
2007-03-13
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Abram, Clare L;Lowell, Clifford A
通讯作者：
Lowell, Clifford A
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
DOI：
10.1073/pnas.1704171114
发表时间：
2017-05-02
影响因子：
11.1
作者：
Li, Jing;Springer, Timothy A.
通讯作者：
Springer, Timothy A.
影响因子：
64.8
作者：
Marshall, BT;Long, M;Zhu, C
通讯作者：
Zhu, C