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Exploring functional and folding energy landscapes by hydrogen-deuterium exchange mass spectrometry.

机译：通过氢-氘交换质谱探索功能性和折叠能态。

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摘要

Alpha-1 antitrypsin (alpha1-AT) is a serine protease inhibitor (serpin) involved in a termination of an inflammation response. An inhibition of a target protease by a serpin alpha1-AT involves a large conformational change, pulling a bound protease from the apex to the opposite pole of the alpha 1-AT molecule, to form a thermodynamically more stable serpin-protease complex. During this large conformational change, the reactive center loop (RCL) of alpha1-AT is inserted between beta-strands 3A and 5A, becoming the fourth strand. It was proposed that the large conformational change during the protease inhibition must be facilitated by the metastability of the native alpha1-AT molecule. Therefore, identifying the sources of the native metastability was an intense focus of previous mutagenesis studies. Although the previous studies attempted to identify destabilizing regions within the native alpha1-AT structure by mutagenesis studies, this study has approached to the same problem from a different aspect -- through an investigation of the protein dynamics using hydrogen-deuterium exchange mass spectrometry (HX-MS). It was found that beta-sheet A in the native metastable form was rigid on the contrary to a suggestion made in previous studies. The same region was also found to be rigid in the intermediate prior to the polymerization indicating that a conformer with the opening of beta-sheet A is probably only transiently populated. This study further discovered that cooperativity exists within the native alpha 1-AT molecule indicating that the opening of beta-sheet A during the inhibition and the polymerization as suggested by previous studies is not possible without affecting other structural regions. In this study, roles of the protein dynamics in the function, folding/unfolding, and polymerization of wild-type alpha1-AT are discussed.
机译：Alpha-1抗胰蛋白酶（alpha1-AT）是一种丝氨酸蛋白酶抑制剂（serpin），参与炎症反应的终止。丝氨酸蛋白酶抑制蛋白α1-AT对靶蛋白酶的抑制涉及大的构象变化，将结合的蛋白酶从顶点拉至α1-AT分子的相反极，以形成热力学上更稳定的丝氨酸蛋白酶-蛋白酶复合物。在这种大的构象变化过程中，α1-AT的反应性中心环（RCL）插入到β链3A和5A之间，成为第四链。有人提出，必须通过天然α1-AT分子的亚稳定性来促进蛋白酶抑制过程中的大构象变化。因此，鉴定天然亚稳定性的来源是先前诱变研究的重点。尽管先前的研究试图通过诱变研究来鉴定天然alpha1-AT结构中的不稳定区域，但该研究从不同方面解决了相同的问题-通过使用氢-氘交换质谱法（HX -多发性硬化症）。发现天然亚稳态形式的β-折叠A是刚性的，这与先前研究中提出的相反。还发现在聚合之前的中间体中相同的区域是刚性的，这表明具有β-折叠A开口的构象异构体可能仅是瞬时填充的。这项研究进一步发现，天然α1-AT分子内存在协同作用，这表明如先前研究所述，在抑制和聚合过程中无法打开β-sheetA而不影响其他结构区域。在这项研究中，讨论了蛋白质动力学在野生型α1-AT的功能，折叠/展开和聚合中的作用。

著录项

  • 作者

    Tsutsui, Yuko.;

  • 作者单位

    Case Western Reserve University.;

  • 授予单位 Case Western Reserve University.;
  • 学科 Biophysics Medical.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 168 p.
  • 总页数 168
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物物理学;
  • 关键词

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