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首页> 外文期刊>Biochemistry >Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region
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Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

机译：对纤维素素抑制剂的纤维素素广泛界面的表征 - 纤溶酶原激活抑制剂-1：内在无序区域中的结构采用

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Small-angle neutron scattering (SANS) measurements were pursued to study human vitronectin, a protein found in tissues and the circulation that regulates cell adhesion/migration and proteolytic cascades that govern hemostasis and pericellular proteolysis. Many of these functions occur via interactions with its binding partner, plasminogen activator inhibitor-1 (PAI-1), the chief inhibitor of proteases that lyse and activate plasminogen. We focused on a region of vitronectin that remains uncharacterized from previous X-ray scattering, nuclear magnetic resonance, and computational modeling approaches and which we propose is involved in binding to PAI-1. This region, which bridges the N-terminal somatomedin B (SMB) domain with a large central beta-propeller domain of vitronectin, appears unstructured and has characteristics of an intrinsically disordered domain (IDD). The effect of osmolytes was evaluated using circular dichroism and SANS to explore the potential of the IDD to undergo a disorder-to-order transition. The results suggest that the IDD favors a more ordered structure under osmotic pressure; SANS shows a smaller radius of gyration (R-g) and a more compact fold of the IDD upon addition of osmolytes. To test whether PAI-1 binding is also coupled to folding within the IDD structure, a set of SANS experiments with contrast variation were performed on the complex of PM-1 with a vitronectin fragment corresponding to the N-terminal 130 amino acids (denoted the SMB-IDD because it contains the SMB domain and IDD in linear sequence). Analysis of the SANS data using the Ensemble Optimization Method confirms that the SMB-IDD adopts a more compact configuration when bound to PAI-1. Calculated structures for the PAI-1:SMB-IDD complex suggest that the IDD provides an interaction surface outside of the primary PM-1-binding site located within the SMB domain; this binding is proposed to lead to the assembly of higher-order structures of vitronectin and PAI-1 commonly found in tissues.
机译：追求小角度中子散射（SAN）测量来研究人体VITRONECTIN，一种在组织中发现的蛋白质和调节细胞粘附/迁移和蛋白水解级联治理止血和围粒体溶液的血液循环。这些功能中的许多功能通过与其结合伴侣的相互作用，纤溶酶原激活剂抑制剂-1（PAI-1），该蛋白酶的主要抑制剂，其溶解和激活纤溶酶原。我们专注于Vitronectin的区域，该区域从先前的X射线散射，核磁共振和计算建模方法保持不协调，我们提出的涉及与PAI-1的结合。该区域桥接具有vitronectin的大中心β-螺旋桨结构蛋白的N-末端体Somatomedin B（SMB）结构域，显影非结构化并且具有本质无序结构域（IDD）的特征。使用圆形二色性和SAN评估渗透肌肉蛋白的效果，以探索IDD的潜力经历令人紊乱的过渡。结果表明，IDD在渗透压下有所有序的结构; SAN在添加渗透物后显示出较小的旋转半径（R-G）和IDD更紧凑的折叠。为了测试PAI-1结合是否也耦合到IDD结构内，在PM-1的复合物上用对应于N-末端130氨基酸的vitronectin片段对具有对比变化的一组具有对比变化的SANS实验（表示SMB-IDD是因为它包含SMB域和线性序列的IDD）。使用集合优化方法分析SAN数据数据确认SMB-IDD在绑定到PAI-1时采用更紧凑的配置。 PAI-1的计算结构：SMB-IDD复合体表明IDD在SMB结构域内的主PM-1结合位点外提供相互作用表面;提出这种结合以导致常见于组织中常见的vitronectin和pai-1的高阶结构的组装。

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