Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18428-32. doi: 10.1073/pnas.1011485107. Epub 2010 Oct 12.
Tetherin/BST2 is a type-II membrane protein that inhibits the release of a range of enveloped viruses, including HIV-1. Here we report 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. However, mutagenesis studies suggest that the tetrametric form of tetherin, although potentially contributing to, is not essential for its antiviral activity. Nonetheless, the structural and chemical properties of the N terminus of the ectodomain are important for optimal tethering function. This study provides detailed insight into the mechanisms by which this broad-spectrum antiviral restriction factor can function.
tetherin/BST2 是一种 II 型膜蛋白，可抑制多种包膜病毒的释放，包括 HIV-1。在此，我们报告了三种人类 tetherin 的晶体结构，包括全长胞外域、三 cysteine 突变体和胞外域截断体。这些结构表明 tetherin 形成一个连续的α螺旋，几乎包含整个胞外域。tetherin 螺旋通过在胞外域的 C 端部分的整个区域的相互作用，二聚形成平行的 coiled coil。对 tetherin 二聚体的多种结构进行比较，揭示了在残基 A88 和 G109 处的两个铰链处存在固有约束的灵活性。在晶体中，两个 tetherin 胞外域二聚体通过在它们的 N 端形成一个反平行的四螺旋束，缔合成四聚体。然而，突变研究表明，tetherin 的四聚体形式虽然可能有助于其抗病毒活性，但并非其必需。尽管如此，胞外域 N 端的结构和化学性质对于最佳的 tethering 功能很重要。本研究深入了解了这种广谱抗病毒限制因子发挥作用的机制。
