PDF(Pubmed)
Abstract：
Cells depend on their endolysosomal system for nutrient uptake and downregulation of plasma membrane proteins. These processes rely on endosomal maturation, which requires multiple membrane fusion steps. Early endosome fusion is promoted by the Rab5 GTPase and its effector, the hexameric CORVET tethering complex, which is homologous to the lysosomal HOPS. How these related complexes recognize their specific target membranes remains entirely elusive. Here, we solve the structure of CORVET by cryo-electron microscopy and revealed its minimal requirements for membrane tethering. As expected, the core of CORVET and HOPS resembles each other. However, the function-defining subunits show marked structural differences. Notably, we discover that unlike HOPS, CORVET depends not only on Rab5 but also on phosphatidylinositol-3-phosphate (PI3P) and membrane lipid packing defects for tethering, implying that an organelle-specific membrane code enables fusion. Our data suggest that both shape and membrane interactions of CORVET and HOPS are conserved in metazoans, thus providing a paradigm how tethering complexes function.
摘要：
细胞依赖于它们的内溶酶体系统来摄取营养和下调质膜蛋白质。这些过程依赖于内体成熟，这需要多个膜融合步骤。Rab5GTPase及其效应物促进早期内体融合，六聚体CORVET系链复合体，与溶酶体HOPS同源。这些相关的复合物如何识别其特定的靶膜仍然是完全难以捉摸的。这里,我们通过低温电子显微镜解决了CORVET的结构，并揭示了其对膜束缚的最低要求。不出所料,Corvet和HOPS的核心相似。然而,功能定义的亚基显示出明显的结构差异。值得注意的是,我们发现不像HOPS,CORVET不仅依赖于Rab5，还依赖于磷脂酰肌醇-3-磷酸（PI3P）和膜脂包装缺陷进行连接，暗示细胞器特异性膜编码能够融合。我们的数据表明，在后生动物中，CORVET和HOPS的形状和膜相互作用都是保守的，从而提供了系链复合体如何发挥作用的范例。
