STRUCTURAL STUDIES OF FOLLISTATIN ISOFORMS BY SAXS IN SOLUTION

通过溶液中的 SAXS 进行卵泡抑素异构体的结构研究

• 批准号: 8362255
• 负责人: CHANGPING ZOU
• 金额: $ 0.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362255
• 关键词: Affinity; Amino Acids; Binding; Binding Sites; C-terminal; Caliber; Characteristics; Exhibits; Follistatin; Funding; Grant; Heparin Binding; Heparitin Sulfate; Ligand Binding; Ligands; Modeling; National Center for Research Resources; Physiological; Principal Investigator; Protein Conformation; Protein Isoforms; Proteins; RNA Splicing; Radiation; Research; Research Infrastructure; Resources; Serum; Shapes; Site; Solutions; Source; Structure; Tail; Testing; Tissues; United States National Institutes of Health; Variant; activin A; base; cost; polypeptide; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Follistatin splice variants, FS288 and FS315, exhibit unique functional and physiological characteristics, such as differences in TGF-b ligand and heparan sulfate binding and serum vs. tissue localization. The addition of 28 amino acids to the FS288 C-terminus may influence follistatin functions by altering the conformation of the protein, thereby decreasing its affinity for both of its known ligands. Based on our analysis of the FS315:activin A crystal structure, we hypothesize that FSD3 may bind to and present the FS315 C-terminal tail to an internal interaction site that overlaps the FSD1 heparin binding site. This model would explain the functional differences between FS isoforms and should be testable using biophysical approaches. In order to influence the ligand binding affinity of FS, the FS315 C-terminus likely induces significant conformational changes in the free FS structure, such as compacting or constraining the structure of the polypeptide chain. The interaction of the tail with the HBS would be predicted to significantly change the shape of the monomeric protein, potentially reducing the overall diameter of the molecule and producing a more globular arrangement of the domains. We propose to test this possibility for the protein in solution using small angle x-ray scattering.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 卵泡抑素剪接变异体FS288和FS315表现出独特的功能和生理特性，例如在转化生长因子-b配体和硫酸肝素结合以及血清和组织定位方面的差异。在FS288C末端增加28个氨基酸可能会通过改变蛋白质的构象来影响卵泡抑素的功能，从而降低其与两个已知配体的亲和力。基于我们对FS315：激活素A晶体结构的分析，我们假设FSD3可能与FS315的C末端结合，并将其呈现给与FSD1肝素结合位点重叠的内部相互作用位点。这个模型将解释FS亚型之间的功能差异，并且应该可以使用生物物理方法进行测试。为了影响FS的配基结合亲和力，FS315的C末端可能会导致游离FS结构的显著构象变化，如紧凑或约束多肽链的结构。预计尾巴与HBS的相互作用将显著改变单体蛋白质的形状，潜在地减小分子的整体直径，并产生更球形的结构域排列。我们建议使用小角X射线散射来测试蛋白质在溶液中的这种可能性。