Biocenter, Medical University Innsbruck, Austria.
EMBO J. 2010 Mar 3;29(5):871-83. doi: 10.1038/emboj.2009.408. Epub 2010 Feb 4.
The sequential action of five distinct endosomal-sorting complex required for transport (ESCRT) complexes is required for the lysosomal downregulation of cell surface receptors through the multivesicular body (MVB) pathway. On endosomes, the assembly of ESCRT-III is a highly ordered process. We show that the length of ESCRT-III (Snf7) oligomers controls the size of MVB vesicles and addresses how ESCRT-II regulates ESCRT-III assembly. The first step of ESCRT-III assembly is mediated by Vps20, which nucleates Snf7/Vps32 oligomerization, and serves as the link to ESCRT-II. The ESCRT-II subunit Vps25 induces an essential conformational switch that converts inactive monomeric Vps20 into the active nucleator for Snf7 oligomerization. Each ESCRT-II complex contains two Vps25 molecules (arms) that generate a characteristic Y-shaped structure. Mutant 'one-armed' ESCRT-II complexes with a single Vps25 arm are sufficient to nucleate Snf7 oligomerization. However, these oligomers cannot execute ESCRT-III function. Both Vps25 arms provide essential geometry for the assembly of a functional ESCRT-III complex. We propose that ESCRT-II serves as a scaffold that nucleates the assembly of two Snf7 oligomers, which together are required for cargo sequestration and vesicle formation during MVB sorting.
五个不同的内体分选复合物所需的运输（ESCRT）复合物的连续作用是通过多泡体（MVB）途径使细胞表面受体在溶酶体下调所必需的。在内体上，ESCRT-III 的组装是一个高度有序的过程。我们表明，ESCRT-III（Snf7）寡聚物的长度控制 MVB 囊泡的大小，并解决了 ESCRT-II 如何调节 ESCRT-III 组装的问题。ESCRT-III 组装的第一步由 Vps20 介导，它引发 Snf7/Vps32 寡聚化，并作为与 ESCRT-II 的连接。ESCRT-II 亚基 Vps25 诱导必需的构象转换，将无活性的单体 Vps20 转化为 Snf7 寡聚化的活性核酶。每个 ESCRT-II 复合物包含两个 Vps25 分子（臂），它们产生特征性的 Y 形结构。具有单个 Vps25 臂的突变“单臂”ESCRT-II 复合物足以引发 Snf7 寡聚化。然而，这些寡聚物不能执行 ESCRT-III 功能。Vps25 的两个臂都为功能性 ESCRT-III 复合物的组装提供了必需的几何形状。我们提出 ESCRT-II 作为核酶引发两个 Snf7 寡聚体组装的支架，这两个寡聚体一起在 MVB 分拣过程中需要货物隔离和囊泡形成。
