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首页> 外文期刊>Biochemistry >Homocysteine Modifies Structural and Functional Properties of Fibronectin and Interferes with the Fibronectin–Fibrillin-1 Interaction
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Homocysteine Modifies Structural and Functional Properties of Fibronectin and Interferes with the Fibronectin–Fibrillin-1 Interaction

机译：同型半胱氨酸修饰纤连蛋白的结构和功能特性，并干扰纤连蛋白– Fibrillin-1的相互作用。

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摘要

Homocystinuria is a genetic disorder resulting innelevated levels of homocysteine in plasma and tissues. Some ofnthe skeletal and ocular symptoms such as long bone overgrowth,nscoliosis, and ectopia lentis overlap with symptoms seen in Marfannsyndrome. Marfan syndrome is caused by mutations in the extracellularnmatrix protein fibrillin-1. We previously showed thatnfibrillin-1 is a target for homocysteine and that the deposition ofnhomocysteinylated fibrillin-1 in the extracellular matrix is compromised.nSince the assembly of fibrillin-1 is critically dependentnon fibronectin, we analyzed the consequences of fibronectinnhomocysteinylation and its interaction with fibrillin-1. Cellularnfibronectin and proteolytic fragments were homocysteinylatednand tested in various interaction assays with recombinant fibrillin-1 and heparin. Fibronectin homocysteinylation consistentlyncompromised the fibronectinu0001fibrillin-1 interaction, while the interaction with heparin was not affected. Fibronectin homocysteinylation,nbut not cysteinylation, reduced the fibronectin dimers to monomers as shown by Western blotting. ELISA analyses ofnhomocysteinylated fibronectin with three monoclonal antibodies demonstrated structural changes in the disulfide-containing FNIndomains FNI2, FNI4, andFNI9. Using fluorescently labeled fibronectin, we studied the consequence of fibronectin homocysteinylationnon assembly in cell culture. Modified fibronectin showed deficiencies in denovo matrix incorporation and initial assembly. Innconclusion, we define here characteristic structural changes of fibronectin upon homocysteinylation that translate into functionalndeficiencies in the fibronectinu0001fibrillin-1 interaction and in fibronectin assembly. Since fibronectin is a major organizer of variousnextracellular protein networks, these structural and functional alterations may contribute to the pathogenesis of homocystinuria andnMarfan syndrome.
机译：同型半胱氨酸尿症是一种遗传性疾病，导致血浆和组织中同型半胱氨酸水平升高。某些骨骼和眼部症状，如长骨过度生长，粘膜病和轻度外翻与马凡氏综合症中所见的症状重叠。 Marfan综合征是由细胞外基质蛋白原纤维蛋白1的突变引起的。先前我们显示nfibrillin-1是高半胱氨酸的靶标，nhomocysteinylated fibrillin-1在细胞外基质中的沉积受到损害.n由于fibrillin-1的组装是关键依赖性的非纤连蛋白，因此我们分析了纤连蛋白nhomocysteinylation及其与纤连蛋白1。细胞半纤连蛋白和蛋白水解片段被同型半胱氨酸修饰，并在多种相互作用测定中与重组纤连蛋白-1和肝素一起进行了测试。纤连蛋白同型半胱氨酸化始终破坏了纤连蛋白u0001fibrillin-1相互作用，而与肝素的相互作用不受影响。如Western印迹所示，纤连蛋白同型半胱氨酸化而不是非半胱氨酸化将纤连蛋白二聚体还原成单体。用三种单克隆抗体对同型半胱氨酸化的纤连蛋白的ELISA分析表明，含二硫键的FNIndomains FNI2，FNI4和FNI9具有结构变化。使用荧光标记的纤连蛋白，我们研究了纤连蛋白同型半胱氨酸化非组装在细胞培养中的结果。修饰的纤连蛋白显示出在树突基质结合和初始组装中的缺陷。结论，我们在这里定义了在半胱氨酸化时纤连蛋白的特征性结构变化，该结构变化转化为纤连蛋白u0001纤丝蛋白-1相互作用和纤连蛋白装配中的功能缺陷。由于纤连蛋白是各种细胞外蛋白网络的主要组织者，因此这些结构和功能的改变可能有助于高半胱氨酸尿症和nMarfan综合征的发病。

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  • 来源
    《Biochemistry》 |2011年第23期|p.5322-5332|共11页
  • 作者

    Dirk Hubmacher Laetitia Sabatier Douglas S. Annis Deane F. Mosher and Dieter P. Reinhardt;

  • 作者单位

    †Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada‡Departments of Biomolecular Chemistry and Medicine, University of Wisconsin, Madison, Wisconsin 53706, United States§Faculty of Dentistry, Division of Biomedical Sciences, McGill University, Montreal, Quebec, Canada;

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