MXRA8

更新于：2025-05-07

基本信息

别名

DKFZp586E2023、Limitrin、matrix remodeling associated 8

+ [2]

简介

Transmembrane protein which can modulate activity of various signaling pathways, probably via binding to integrin ITGAV:ITGB3 (PubMed:22492581, PubMed:23386276). Mediates heterophilic cell-cell interactions in vitro (By similarity). Inhibits osteoclastogenesis downstream of TNFSF11/RANKL and CSF1, where it may function by attenuating signaling via integrin ITGB3 and MAP kinase p38 (By similarity). Plays a role in cartilage formation where it promotes proliferation and maturation of growth plate chondrocytes (By similarity). Stimulates formation of primary cilia in chondrocytes (By similarity). Enhances expression of genes involved in the hedgehog signaling pathway in chondrocytes, including the hedgehog signaling molecule IHH; may also promote signaling via the PTHLH/PTHrP pathway (By similarity). Plays a role in angiogenesis where it suppresses migration of endothelial cells and also promotes their apoptosis (PubMed:23386276). Inhibits VEGF-induced activation of AKT and p38 MAP kinase in endothelial cells (PubMed:23386276). Also inhibits VTN (vitronectin)-mediated integrin ITGAV:ITGB3 signaling and activation of PTK2/FAK (PubMed:23386276). May play a role in the maturation and maintenance of the blood-brain barrier (By similarity). (Microbial infection) Contributes to arthritogenic alphavirus pathogenesis and acts as a receptor for these viruses.

关联

项与 MXRA8 相关的药物

US20240124553

专利挖掘

靶点

MXRA8

作用机制-

在研机构

Washington University in St. Louis

原研机构

Washington University in St. Louis

在研适应症

感染 [+1]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MXRA8 相关的临床结果

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100 项与 MXRA8 相关的转化医学

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0 项与 MXRA8 相关的专利（医药）

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项与 MXRA8 相关的文献（医药）

2024-07-23·Journal of Virology

Changes in the chikungunya virus E1 glycoprotein domain II and hinge influence E2 conformation, infectivity, and virus-receptor interactions

Article

作者: Thannickal, Sara A ; Noval, Maria G ; Battini, Leandro ; Spector, Sophie N ; Álvarez, Diego E ; Stapleford, Kenneth A

ABSTRACT In a previous study to understand how the chikungunya virus (CHIKV) E1 glycoprotein β-strand c functions, we identified several attenuating variants at E1 residue V80 and the emergence of second-site mutations in the fusion loop (E1-M88L) and hinge region (E1-N20Y) with the V80 variants in vivo . The emergence of these mutations led us to question how changes in E1 may contribute to CHIKV infection at the molecular level. Here, we use molecular dynamics to understand how changes in the E1 glycoprotein may influence the CHIKV glycoprotein E1-E2 complex. We found that E1 domain II variants lead to E2 conformational changes, allowing us to hypothesize that emerging variants E1-M88L and E1-N20Y could also change E2 conformation and function. We characterized CHIKV E1-M88L and E1-N20Y in vitro and in vivo to understand how these regions of the E1 glycoprotein contribute to host-specific infection. We found that CHIKV E1-N20Y enhanced infectivity in mosquito cells, while the CHIKV E1-M88L variant enhanced infectivity in both BHK-21 and C6/36 cells and led to changes in viral cholesterol-dependence. Moreover, we found that E1-M88L and E1-N20Y changed E2 conformation, heparin binding, and interactions with the receptor Mxra8. Interestingly, the CHIKV E1-M88L variant increased replication in Mxra8-deficient mice compared to WT CHIKV, yet was attenuated in mouse fibroblasts, suggesting that residue E1-M88 may function in a cell-type-dependent entry. Taken together, these studies show that key residues in the CHIKV E1 domain II and hinge region function through changes in E1-E2 dynamics to facilitate cell- and host-dependent entry. IMPORTANCE Arboviruses are significant global public health threats, and their continued emergence around the world highlights the need to understand how these viruses replicate at the molecular level. The alphavirus glycoproteins are critical for virus entry in mosquitoes and mammals, yet how these proteins function is not completely understood. Therefore, it is critical to dissect how distinct glycoprotein domains function in vitro and in vivo to address these gaps in our knowledge. Here, we show that changes in the CHIKV E1 domain II and hinge alter E2 conformations leading to changes in virus-receptor and -glycosaminoglycan interactions and cell-specific infection. These results highlight that adaptive changes in E1 can have a major effect on virus attachment and entry, furthering our knowledge of how alphaviruses infect mammals and insects.

2024-05-01·Obesity

Plasma proteomic profile of abdominal obesity in older adults

Article

作者: Ayers, Emmeline ; Gao, Tina ; Barzilai, Nir ; Verghese, Joe ; Sathyan, Sanish ; Milman, Sofiya

AbstractObjectiveThis study examines the plasma proteomic profile of abdominal obesity in older adults.MethodsThe association of abdominal obesity (waist circumference [WC]) with 4265 plasma proteins identified using the SomaScan Assay was examined in 969 Ashkenazi Jewish participants (LonGenity cohort), aged 65 years and older (mean [SD] age 75.7 [6.7] years, 55.4% women), using regression models. Pathway analysis, as well as weighted correlation network analysis, was performed. WC was determined from the proteome using elastic net regression.ResultsA total of 480 out of 4265 proteins were associated with WC in the linear regression model. Leptin (β [SE] = 12.363 [0.490]), inhibin β C chain (INHBC; β [SE] = 24.324 [1.448]), insulin‐like growth factor‐binding protein 2 (IGFBP‐2; β [SE] = −12.782 [0.841]), heparan‐sulfate 6‐O‐sulfotransferase 3 (H6ST3; β [SE] = −39.995 [2.729]), and matrix‐remodeling‐associated protein 8 (MXRA8; β [SE] = −27.101 [1.850]) were the top proteins associated with WC. Cell adhesion, extracellular matrix remodeling, and IGF transport pathways were the top enriched pathways associated with WC. WC signature determined from plasma proteins was highly correlated with measured WC (r = 0.80) and was associated with various metabolic and physical traits.ConclusionsThe study unveiled a multifaceted plasma proteomic profile of abdominal obesity in older adults, offering insights into its wide‐ranging impact on the proteome. It also elucidated novel proteins, clusters of correlated proteins, and pathways that are intricately associated with abdominal obesity.

2023-11-24·Oncogene

STT3A-mediated viral N-glycosylation underlies the tumor selectivity of oncolytic virus M1

Article

作者: Zhang, Qinfen ; Yan, Guangmei ; Hu, Jun ; Gao, Yuanzhu ; Jia, Xudong ; Shen, Runling ; Zhu, Wenbo ; Song, Deli ; Liang, Jiankai ; Xiao, Tong ; Lin, Yuan ; Cai, Jing ; Dan, Jia

Oncolytic viruses are emerging as promising anticancer agents. Although the essential biological function of N-glycosylation on viruses are widely accepted, roles of N-glycan and glycan-processing enzyme in oncolytic viral therapy are remain elusive. Here, via cryo-EM analysis, we identified three distinct N-glycans on the envelope of oncolytic virus M1 (OVM) as being necessary for efficient receptor binding. E1-N141-glycan has immediate impact on the binding of MXRA8 receptor, E2-N200-glycan mediates the maturation of E2 from its precursor PE2 which is unable to bind with MXRA8, and E2-N262-glycan slightly promotes receptor binding. The necessity of OVM N-glycans in receptor binding make them indispensable for oncolysis in vitro and in vivo. Further investigations identified STT3A, a key catalytic subunit of oligosaccharyltransferase (OST), as the determinant of OVM N-glycosylation, and STT3A expression in tumor cells is positively correlated with OVM-induced oncolysis. Increased STT3A expression was observed in various solid tumors, pointing to a broad-spectrum anticancer potential of OVM. Collectively, our research supports the importance of STT3A-mediated N-glycosylation in receptor binding and oncolysis of OVM, thus providing a novel predictive biomarker for OVM.

项与 MXRA8 相关的新闻（医药）

2023-12-01

·生物探索

MXRA8诱饵分子可防止甲病毒感染

圣路易斯华盛顿大学医学院的研究人员发现了一种创新的方法，可以用于阻止多种甲病毒（又称阿尔法病毒）的感染。甲病毒是一组由蚊子传播的病毒，可导致人类关节（如：基孔肯雅病毒）和大脑感染（如：委内瑞拉马脑炎病毒，西方马脑炎病毒、东方马脑炎病毒等）。甲病毒颗粒被包裹，直径为70nm，趋于呈球形，并具有大小为40nm的等距几何体衣壳。这项研究由医学教授Michael S. Diamond和病理学和免疫学教授Daved H. Fremont领导，有望成为开发针对不常见但严重感染疾病的谱疗法的第一步。该论文近期发表在《细胞》杂志上。Michael S. Diamond说：“甲病毒在世界各地造成了巨大的疾病负担，而目前没有任何抗病毒药物可以治疗它们。因此，我们的研究开展有望满足日渐迫切的治疗需求。”大多数使人患病的甲病毒属于两个亚组之一：引起脑炎的甲病毒和引起关节炎的甲病毒。在之前的一项研究中，Diamond、Fremont及其同事发现，引起关节炎的病毒通过附着在一种名为MXRA8的分子上进入人类和小鼠细胞。在这项新研究中他们发现，一些引起脑炎的甲病毒也通过附着MXRA8来侵入细胞，但只能附着在鸟类的MXRA8，而无法附着在哺乳动物的MXRA8上。诱饵分子合成过程（图源：Cell 2023. DOI: 10.1016/j.cell.2023.09.007）研究人员将禽类（特别是鸭子）和哺乳动物（小鼠）的MXRA8进行了部分融合，创造了一种诱饵分子。这种诱饵可以中和引起脑炎或关节炎的甲病毒，保护小鼠免受感染，表明了其作为治疗的发展潜力。参考文献：Ofer Zimmerman et al, Vertebrate-class-specific binding modes of the alphavirus receptor MXRA8, Cell (2023). DOI: 10.1016/j.cell.2023.09.007责编|探索君排版|探索君End往期精选围观科学家称，每25人中就有1人携带“短寿”基因热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文肝癌概率与种族相关？研究发现墨西哥裔美国人后代肝癌患病风险更高热文1型糖尿病潜在新疗法：抑制β细胞的Atf6基因激活热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

临床研究

2023-04-28

·生物谷

清华大学医学院向烨/中国科学院章新政团队合作揭示甲病毒的新型受体识别模式及跨物种传播机制

甲病毒（alphavirus）是一类由蚊虫等节肢动物传播的、有囊膜、单链、正义RNA病毒，属于披膜病毒科（Togaviridae），能广泛感染人、鸟、鼠、马等多种动物并引起相关疾病。甲病毒感染人类后可甲病毒（alphavirus）是一类由蚊虫等节肢动物传播的、有囊膜、单链、正义RNA病毒，属于披膜病毒科（Togaviridae），能广泛感染人、鸟、鼠、马等多种动物并引起相关疾病。甲病毒感染人类后可引起发烧、严重且持续的头痛、肌肉疼痛和关节痛。一些甲病毒能感染神经细胞并导致中枢神经系统感染，引发重症脑炎[1]。迄今为止，还没有任何药物或者疫苗被批准用来治疗或者预防甲病毒的感染。近年来，关于甲病毒侵染机制的研究已有一系列重要进展。基孔肯雅热病毒（CHIKV）与其受体Mxra8（matrix remodeling associated protein 8）结合的分子机制和委内瑞拉马脑炎病毒（VEEV）与其受体LDLRAD3（Low-density lipoprotein receptor class A domain-containing protein 3）结合的分子机制均已清晰阐明[2-5]。然而根据现有研究尚不能解释甲病毒能广泛感染从非脊椎动物到脊椎动物、且进化关系上跨度很大的多种物种的原因。2021年的一篇研究报道表明载脂蛋白受体VLDLR（very-low-density lipoprotein receptor）是多种甲病毒，包括塞姆利基森林病毒（Semliki Forest Virus, SFV），感染蚊虫、鼠、马、人等多个物种的通用受体[6]。介导病毒跨越差异极大的不同物种之间传播的通用受体鲜有报道，病毒与这类受体的结合模式及其介导的跨物种传播机制尚不清楚。 2023年4月24日，《Cell》杂志在线发表了清华大学医学院向烨课题组和中国科学院生物物理研究所章新政课题组合作完成的研究论文“Structure of Semliki Forest virus in complex with its receptor VLDLR”。该工作解析了SFV与人源受体VLDLR复合物的高分辨率冷冻电镜结构，鉴定了一种甲病毒全新的受体结合位点，揭示了受体VLDLR的多个相似串联结构域通过协同作用与SFV特异性结合的新型机制。该研究首次阐释了通用受体分子介导病毒实现跨物种传播的分子机制，为抗病毒药物设计及新型疫苗开发提供了新靶点。甲病毒囊膜表面有80个三聚体形式的刺突蛋白spike，每个spike由三个E1/E2异源二聚体构成。已有研究普遍认为位于Spike近囊膜区域的E1主要负责病毒与宿主的膜融合，而位于病毒远离囊膜区域spike上的E2参与受体结合[7]。CHIKV与MXRA8复合物和VEEV与LDLRAD3复合物结构研究发现，LDLRAD3和MXRA8都结合在病毒spike上相邻E1-E2二聚体形成的狭缝中，病毒的E1、E2蛋白均参与了与受体的结合[2-5]。在本研究中，研究人员利用基于分块重构算法的单颗粒冷冻电镜技术，成功解析了SFV VLP及其与受体VLDLR复合物的高分辨率结构，并出乎意料的发现VLDLR结合在SFV E1蛋白贴近囊膜区域的DⅢ结构域（E1-DⅢ）上，且 SFV E2并没有参与和受体VLDLR的结合。这种结合方式与以往发现的甲病毒受体结合方式完全不同，刷新了关于甲病毒与受体相互作用的认知。研究团队进一步发现VLDLR通过其胞外多个富含半胱氨酸重复序列结构域(LDLR class A repeats，LAs)与SFV E1-DⅢ结合。单个LA结构域与病毒的结合力弱，其解离常数为1-30 uM，而多个串联LA结构域与病毒的结合显著增强，其解离常数为1-100 nM。SFV表面受体结合位置E1-DⅢ在二次轴、五次轴附近相互靠近且密集排布，为多个LA结构域可能的协同结合提供了先决条件。通过解析SFV VLP与多个串联LA复合物结构，研究团队发现多个串联的LAs可同时结合SFV VLP多个E1-DIII位点，而且存在多种不同的结合模式（图1）。在五次轴附近，多个串联LAs发生轻微的旋转避免空间上的阻碍以便协同结合E1-DⅢ。与单个LA结合时相比，串联形式中的LA虽然在转动过程中大部分与E1-DⅢ的相互作用会被破坏，但是一些关键位点上的相互作用依旧保留着，而且通过串联LAs的协同作用，弥补了单个LA上非关键性相互作用的损失，大大增强了病毒与受体的结合力。从而，这种多个串联LA协同作用模式能够增加受体对单个LA中结合能力丢失的容忍度。不同物种VLDLR大多数LA序列虽然差异较大，但与病毒作用关键残基W132、E137和D139完全保守。VLDLR独特的协同结合模式，使其在介导病毒感染时能够耐受来自不同进化层次物种间序列的差异，实现跨度很大的多物种之间的病毒传播。综上，该研究通过结构生物学手段，结合多种生化方法，首次阐述了多种宿主中进化上相对保守的通用细胞受体通过其多个相似结构域弱相互作用的协同工作与病毒特异性结合，从而介导病毒跨物种入侵的分子机制。图1. 新型受体通过多个串联LA结构域的协同作用介导甲病毒SFV的跨物种传播清华大学医学院向烨研究员和中国科学院生物物理研究所章新政研究员为该论文的共同通讯作者，章新政课题组副研究员曹端方、向烨课题组博士后马丙婷和章新政课题组博士研究生曹紫怡为该论文的共同第一作者。这项工作得到了科技部重点研发项目、清华大学万科公共卫生与健康学科发展专项基金、国家自然科学基金、清华大学春风基金、北京生物结构前沿研究中心、中国科学院战略重点研究计划、中国科学院前沿科学重点研发计划和中科院青年创新促进会的基金支持。论文链接：https://authors.elsevier.com/a/1gzV3_278y%7ETQf Reference: [1] WEAVER S C, BARRETT A D. Transmission cycles, host range, evolution and emergence of arboviral disease [J]. Nat Rev Microbiol, 2004, 2(10): 789-801. [2] MA B, HUANG C, MA J, et al. Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3 [J]. Nature, 2021, 598(7882): 677-81. [3] BASORE K, MA H, KAFAI N M, et al. Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor [J]. Nature, 2021, 598(7882): 672-6. [4] SONG H, ZHAO Z, CHAI Y, et al. Molecular basis of arthritogenic alphavirus receptor MXRA8 binding to chikungunya virus envelope protein [J]. Cell, 2019, 177(7): 1714-24. e12. [5] BASORE K, KIM A S, NELSON C A, et al. Cryo-EM structure of chikungunya virus in complex with the Mxra8 receptor [J]. Cell, 2019, 177(7): 1725-37. e16. [6] CLARK L E, CLARK S A, LIN C, et al. VLDLR and ApoER2 are receptors for multiple alphaviruses [J]. Nature, 2021. [7] JOSE J, SNYDER J E, KUHN R J. A structural and functional perspective of alphavirus replication and assembly [J]. Future Microbiol, 2009, 4(7): 837-56.