VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.
Mol Cell. 2018 Sep 6;71(5):689-702.e9. doi: 10.1016/j.molcel.2018.07.016.
Hsp90 is an essential chaperone that guards proteome integrity and amounts to 2% of cellular protein. We now find that Hsp90 also has the ability to directly interact with and deform membranes via an evolutionarily conserved amphipathic helix. Using a new cell-free system and in vivo measurements, we show this amphipathic helix allows exosome release by promoting the fusion of multivesicular bodies (MVBs) with the plasma membrane. We dissect the relationship between Hsp90 conformation and membrane-deforming function and show that mutations and drugs that stabilize the open Hsp90 dimer expose the helix and allow MVB fusion, while these effects are blocked by the closed state. Hence, we structurally separated the Hsp90 membrane-deforming function from its well-characterized chaperone activity, and we show that this previously unrecognized function is required for exosome release.
热休克蛋白 90（Hsp90）是一种重要的伴侣蛋白，可保护蛋白质组的完整性，约占细胞总蛋白的 2%。我们现在发现，Hsp90 还具有通过一个进化上保守的两亲性螺旋与膜直接相互作用并使其变形的能力。使用新的无细胞系统和体内测量，我们表明这种两亲性螺旋通过促进多泡体（MVB）与质膜融合来促进外泌体的释放。我们剖析了 Hsp90 构象与膜变形功能之间的关系，并表明使开放的 Hsp90 二聚体稳定的突变和药物会暴露该螺旋并允许 MVB 融合，而这些效应会被封闭状态所阻断。因此，我们从其特征明确的伴侣活性中结构上分离了 Hsp90 的膜变形功能，并表明该以前未被识别的功能是外泌体释放所必需的。
