Park Heather E, Gruenke Jennifer A, White Judith M
Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Nat Struct Biol. 2003 Dec;10(12):1048-53. doi: 10.1038/nsb1012. Epub 2003 Nov 2.
Formation of helix bundles has been proposed as a general mechanism for viral and cellular membrane fusion reactions. Class I viral fusion proteins, including HIV Env and influenza hemagglutinin (HA), form six-helix bundles in their fusogenic forms. The HIV Env six-helix bundle extends to the membrane proximal end of the protein, where it is poised to pull the fusing membranes together. In contrast, the HA six-helix bundle is located at the membrane distal end of the protein. It is followed by a C-terminal 'leash' that packs into the grooves and extends to the membrane proximal end of the coiled-coil. Here, we describe the ability of C-terminal leash mutants to change conformation and induce fusion. Our data indicate that packing of the C-terminal leash into the grooves of the coiled-coil is necessary for HA to mediate the lipid mixing stage of fusion, and that hydrophobic membrane proximal leash residues secure this interaction. Therefore, HA employs a 'leash in the groove,' rather than a helix-bundle, mechanism of membrane fusion.
螺旋束的形成已被提出作为病毒和细胞膜融合反应的一种普遍机制。I类病毒融合蛋白，包括HIV包膜蛋白（Env）和流感血凝素（HA），在其融合形式下形成六螺旋束。HIV Env六螺旋束延伸到蛋白质的膜近端，在那里它准备将融合的膜拉到一起。相比之下，HA六螺旋束位于蛋白质的膜远端。随后是一个C端“ leash”，它包装到凹槽中并延伸到卷曲螺旋的膜近端。在这里，我们描述了C端leash突变体改变构象并诱导融合的能力。我们的数据表明，C端leash包装到卷曲螺旋的凹槽中对于HA介导融合的脂质混合阶段是必要的，并且疏水性膜近端leash残基确保了这种相互作用。因此，HA采用“凹槽中的leash”而不是螺旋束的膜融合机制。
