STRUCTURAL STUDY OF DISEASE RELATED FACTORS

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。 Tetherin/BST2是一种II型膜蛋白，可以抑制包括HIV-1在内的一系列包膜病毒的释放。我们解决了人类tetherin的三种晶体结构，包括全长的胞外结构域，一个三重半胱氨酸突变体和一个胞外结构域截断。这些结构表明，Tetherin形成了一个连续的α螺旋，几乎覆盖了整个胞外结构域。Tetherin螺旋通过相互作用在胞外结构域的C-末端部分聚合成平行的盘绕线圈。对Tetherin二聚体的多种结构的比较揭示了位于残基A88和G109的两个铰链上固有的受限灵活性。在晶体中，两个Tetherin胞外结构域二聚体通过在它们的N末端形成一个反平行的四螺旋束而结合成一个四聚体。这项研究为这种广谱抗病毒限制因子发挥作用的机制提供了详细的见解。

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. Tetherin/BST2 is a type-II membrane protein that inhibits the release of a range of enveloped viruses, including HIV-1. We solved three crystal structures of human tetherin, including the full-length ectodomain, a triple cysteine mutant and an ectodomain truncation. These structures show that tetherin forms a continuous alpha helix encompassing almost the entire ectodomain. Tetherin helices dimerize into parallel coiled coils via interactions throughout the C-terminal portion of the ectodomain. A comparison of the multiple structures of the tetherin dimer reveals inherent constrained flexibility at two hinges positioned at residues A88 and G109. In the crystals, two tetherin ectodomain dimers associate into a tetramer by forming an antiparallel four-helix bundle at their N termini. This study provides detailed insight into the mechanisms by which this broad-spectrum antiviral restriction factor can function.