• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Molecular Biology >An inhibitory antibody blocks the first step in the dithiol/disulfide relay mechanism of the enzyme QSOX1
【24h】

An inhibitory antibody blocks the first step in the dithiol/disulfide relay mechanism of the enzyme QSOX1

机译：抑制性抗体阻断了QSOX1酶的二硫醇/二硫键中继机制的第一步

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Quiescin sulfhydryl oxidase 1 (QSOX1) is a catalyst of disulfide bond formation that undergoes regulated secretion from fibroblasts and is over-produced in adenocarcinomas and other cancers. We have recently shown that QSOX1 is required for incorporation of particular laminin isoforms into the extracellular matrix (ECM) of cultured fibroblasts and, as a consequence, for tumor cell adhesion to and penetration of the ECM. The known role of laminins in integrin-mediated cell survival and motility suggests that controlling QSOX1 activity may provide a novel means of combating metastatic disease. With this motivation, we developed a monoclonal antibody that inhibits the activity of human QSOX1. Here, we present the biochemical and structural characterization of this antibody and demonstrate that it is a tight-binding inhibitor that blocks one of the redox-active sites in the enzyme, but not the site at which de novo disulfides are generated catalytically. Sulfhydryl oxidase activity is thus prevented without direct binding of the sulfhydryl oxidase domain, confirming the model for the interdomain QSOX1 electron transfer mechanism originally surmised based on mutagenesis and protein dissection. In addition, we developed a single-chain variant of the antibody and show that it is a potent QSOX1 inhibitor. The QSOX1 inhibitory antibody will be a valuable tool in studying the role of ECM composition and architecture in cell migration, and the recombinant version may be further developed for potential therapeutic applications based on manipulation of the tumor microenvironment.
机译：Quiescin巯基氧化酶1（QSOX1）是二硫键形成的催化剂，其受成纤维细胞分泌的调节，在腺癌和其他癌症中过量产生。我们最近显示，QSOX1是将特定层粘连蛋白同工型掺入培养的成纤维细胞的细胞外基质（ECM）中所必需的，因此，肿瘤细胞对ECM的粘附和渗透也需要QSOX1。层粘连蛋白在整联蛋白介导的细胞存活和运动中的已知作用表明，控制QSOX1活性可能为对抗转移性疾病提供了一种新颖的手段。以此动机，我们开发了一种抑制人QSOX1活性的单克隆抗体。在这里，我们介绍了该抗体的生化和结构特征，并证明它是一种紧密结合的抑制剂，可阻断酶中的氧化还原活性位点之一，但不会催化从头产生二硫化物的位点。因此，在没有巯基氧化酶结构域的直接结合的情况下，可以防止巯基氧化酶的活性，从而证实了最初基于诱变和蛋白质解剖学推测的域间QSOX1电子转移机制的模型。此外，我们开发了该抗体的单链变体，并显示它是有效的QSOX1抑制剂。 QSOX1抑制性抗体将是研究ECM组成和结构在细胞迁移中的作用的有价值的工具，并且可以基于对肿瘤微环境的操纵，进一步开发重组版本以用于潜在的治疗应用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号