CD44增强E-选择素与PSGL-1配体互作的结构基础

目的选择素-体相互作用在炎症级联反应过程中起重要作用。E-选择素由于具有多种配体,而且不同配体间存在协同作用,从而导致其在炎症级联反应过程中的作用更为复杂。PSGL-1、CD44作为E-选择素的典型配体,二者间存在协同作用,但机制尚不清楚,且E-选择素-D44相互作用的微观结构特征也尚无报道。因此

Multi-scale molecular dynamics simulations and applications on mechanosensitive proteins of integrins*

Molecular dynamics simulation (MDS) is a powerful technology for investigating evolution dynamics of target proteins, and it is used widely in various fields from materials to biology. This mini-review introduced the principles, main preforming procedures, and advances of MDS, as well as its applications on the studies of conformational and allosteric dynamics of proteins especially on that of the mechanosensitive integrins. Future perspectives were also proposed. This review could provide clues in understanding the potentiality of MD simulations in structure-function relationship investigation of biological proteins

CD44与不同分子量HA相互作用的差异以及对细胞黏附的影响

目的 CD44是一种I型跨膜糖蛋白,广泛分布于肿瘤细胞、免疫细胞、干细胞等,其与配体的相互作用介导细胞基质互作和细胞与细胞黏附。透明质酸HA是CD44的重要配体之一,二者相互作用在介导肝脏免疫反应中具有重要作用,其生物学功能与HA分子量密切相关。已有研究表明,低分子量HA促进炎症,而高分子量HA则抑制炎症。因此,探究CD44与不同分子量HA的相互作用对于理解上述生物学功能具有重要意义

E-选择素负向调控中性粒细胞跨内皮迁移的生物力学机制

目的以血管稳态及重建为切入点,研究E-选择素(E-selectin)通过调节微丝骨架网络的动态重组来调控内皮细胞胞间连接整合性,从而促进中性粒细胞跨内皮迁移的信号调控网络和关键分子。方法建立体外人中性粒细胞(PMN)在脂多糖处理的人脐静脉内皮细胞单层上跨内皮迁移动力学模型,通过原子力显微镜、活细胞成像、蛋白免疫印迹、邻位连接等手段检测内皮细胞胞间连接整合性。结果PMN在E-selectin敲低的内皮细胞上表现出更快、更高的跨内皮迁移动力学能力

E-选择素负向调控中性粒细胞跨内皮迁移的生物力学机制

目的以血管稳态及重建为切入点,研究E-选择素(E-selectin)通过调节微丝骨架网络的动态重组来调控内皮细胞胞间连接整合性,从而促进中性粒细胞跨内皮迁移的信号调控网络和关键分子。方法建立体外人中性粒细胞(PMN)在脂多糖处理的人脐静脉内皮细胞单层上跨内皮迁移动力学模型,通过原子力显微镜、活细胞成像、蛋白免疫印迹、邻位连接等手段检测内皮细胞胞间连接整合性。结果PMN在E-selectin敲低的内皮细胞上表现出更快、更高的跨内皮迁移动力学能力

CD44与其配体E-选择素及HA的差异性相互作用

目的位的募集过程中起重要作用。已有研究表明,E-选择素与HA分别可以通过与CD44的相互作用启动整合素LFA-1和VLA4的激活,但是其内在机制尚不清楚。方法 采用原子力显微镜及流动腔技术分别从分子与细胞层次定量考察CD44与E-选择素/HA相互作用的差异,通过分子对接技术从原子层次考察CD44与E-选择素/HA相互作用的微观结构差异。结果 原子力显微镜结果表明,E-选择素与CD44的相互作用力及负反应率均高于HA。流动腔结果表明,表面表达CD44的U937细胞在底板包被E-选择素的条件下呈现稳定"滚动";而在底板包被H

E-selectin negatively regulates polymorphonuclear neutrophil transmigration through altered endothelial junction integrity

Transendothelial migration (TEM) of neutrophils under blood flow is critical in the inflammatory cascade. However, the role of endothelial plasticity in this process is not fully understood. Therefore, we used an in vitro model to test the dynamics of human polymorphonuclear neutrophil (PMN) TEM across lipopolysaccharide-treated human umbilical vein endothelial cell (HUVEC) monolayers. Interestingly, shRNA-E-selectin knockdown in HUVECs destabilized endothelial junctional integrity by reducing actin branching and increasing stress fiber at cell-cell junctions. This process is accomplished by downregulating the activation of cortactin and Arp2/3, which in turn alters the adhesive function of VE-cadherin, enhancing PMN transmigration. Meanwhile, redundant P-selectins possess overlapping functions in E-selectin-mediated neutrophil adhesion, and transmigration. These results demonstrate, to our knowledge, for the first time, that E-selectins negatively regulate neutrophil transmigration through alterations in endothelial plasticity. Furthermore, it improves our understanding of the mechanisms underlying actin remodeling, and junctional integrity, in endothelial cells mediating leukocyte TEM

CD44-配体相互作用的生物力学与功能调控

作为一种广谱表达的细胞粘附分子, I型跨膜糖蛋白CD44(cluster of differentiation 44)参与细胞增殖、分化、迁移,血管生成等生物学过程,对于介导细胞信号转导,调节组织稳态等功能具有关键作用.特别地, CD44-选择素、CD44-透明质酸相互作用介导的细胞粘附动力学在经典炎症反应、肿瘤转移或组织特异的肝脏免疫中具有重要作用.该综述分别从细胞层次粘附动力学、二维与三维条件下的分子层次反应动力学、原子层次微观结构以及胞内信号转导通路等方面综述了CD44-选择素、CD44-透明质酸相互作用的研究进展及尚待回答的生物力学问题.力学、物理因素对生命活动的不可或缺性逐渐被研究者们接受,力学医学、力学免疫学、力学组学等新概念相继提出.生理、病理条件下, CD44-配体相互作用介导的细胞粘附必将受到血流剪切、基底硬度等力学、物理微环境的调控,但是其调控机制还远不清楚.基于此,本文就CD44-配体相互作用相关的未来研究方向做出展望,主要包括:力学、物理因素如何调控CD44-配体相互作用介导的细胞粘附动力学及其内在机制;CD44-配体相互作用反应动力学的力学调控规律及结构基础是什么;以及力学作用下CD44-配体相互作用原子层次的微观结构如何发生动态演化.本文可为深入理解CD44-配体相互作用的生物学功能及其结构功能关系提供线索

Distinct binding kinetics of E-, P- and L-selectins to CD44

Molecular-level selectin-cluster of differentiation 44 (CD44) interactions are far from clear because of the complexity and diversity of CD44 glycosylation and isoforms expressed on various types of cells. By combining experimental measurements and simulation predictions, the binding kinetics of three selectin members to the recombinant CD44 were quantified and the corresponding microstructural mechanisms were explored, respectively. Experimental results showed that the E-selectin-CD44 interactions mainly mediated the firm adhesion of microbeads under shear flow with the strongest rupture force. P- and L-selectins had similar interaction strength but different association and dissociation rates by mediating stable rolling and transient adhesions of microbeads, respectively. Molecular docking and molecular dynamics (MD) simulations predicted that the binding epitopes of CD44 to selectins are all located at the side face of each selectin, although the interfaces denoted as the hinge region are between lectin and epidermal growth factor domains of E-selectin, Lectin domain side of P-selectin and epidermal growth factor domain side of L-selectin, respectively. The lowest binding free energy, the largest rupture force and the longest lifetime for E-selectin, as well as the comparable values for P- and L-selectins, demonstrated in both equilibration and steered MD simulations, supported the above experimental results. These results offer basic data for understanding the functional differences of selectin-CD44 interactions