FCH domain only-2 organizes clathrin-coated structures and interacts with Disabled-2 for low-density lipoprotein receptor endocytosis.
FCH domain only-2 organizes clathrin-coated structures and interacts with Disabled-2 for low-density lipoprotein receptor endocytosis.
复制标题
DOI：
10.1091/mbc.e11-09-0812
复制
发表时间：
2012-04
影响因子：
3.3
通讯作者：
Cooper JA
中科院分区：
文献类型：
--
作者：
Mulkearns EE;Cooper JA
网格蛋白接头 Disabled-2 (Dab2) 与 F-BAR 蛋白 FCH 结构域 only-2 (FCHO2) 相互作用，当 AP2 水平较低时，这种相互作用对于 Dab2 功能是必需的。 FCHO2 调节网格蛋白结构的大小并在受体招募中发挥作用。我们的结果表明，FCHO2 对于包被坑的起始不是必需的，但可以调节包被坑的大小和功能。网格蛋白介导的内吞作用调节许多营养和信号受体的内化。网格蛋白和内吞辅助蛋白通过特定的接头被招募到受体上。即使主要接头蛋白 AP2 耗尽，接头 Disabled-2 (Dab2) 也会招募其货物，包括低密度脂蛋白受体 (LDLR)，并介导内吞作用。我们假设，如果 AP2 不存在，通常由 AP2 募集的辅助蛋白可能会被 Dab2 募集。我们鉴定了一种这样的辅助蛋白，即 F-BAR 蛋白 FCH 仅结构域 2 (FCHO2)，作为主要的 Dab2 相互作用蛋白。 FCHO2 的 μ 同源结构域 (μHD) 直接与 Dab2 中的 DPF 序列结合，Dab2 中的 DPF 序列也与 AP2 结合。在 AP2 耗尽的细胞中，破坏 Dab2-FCHO2 相互作用可抑制 Dab2 介导的 LDLR 内吞作用。耗尽 FCHO2 会减少 HeLa 细胞粘附表面网格蛋白结构的数量，但增加其大小，并抑制 LDLR 和转铁蛋白受体聚集。然而，当在出芽前为 LDLR 提供额外的时间进入扩大的结构时，LDLR 被 FCHO2 缺陷细胞有效内化，这表明在这些条件下，内吞作用的后续步骤是正常的。这些结果表明 FCHO2 调节网格蛋白结构的大小，并且在低 AP2 条件下，FCHO2 与 Dab2 的相互作用是 LDLR 内吞作用所必需的。
The clathrin adaptor Disabled-2 (Dab2) interacts with the F-BAR protein FCH domain only-2 (FCHO2), and this interaction is necessary for Dab2 function when AP2 levels are low. FCHO2 regulates the size of clathrin structures and plays a role in receptor recruitment. Our results indicate that FCHO2 is not essential for coated pit initiation but regulates coated pit size and function. Clathrin-mediated endocytosis regulates the internalization of many nutrient and signaling receptors. Clathrin and endocytic accessory proteins are recruited to receptors by specific adaptors. The adaptor Disabled-2 (Dab2) recruits its cargoes, including the low-density lipoprotein receptor (LDLR), and mediates endocytosis, even when the major adaptor protein AP2 is depleted. We hypothesized that the accessory proteins normally recruited by AP2 may be recruited by Dab2 if AP2 is absent. We identified one such accessory protein, the F-BAR protein FCH domain only-2 (FCHO2), as a major Dab2-interacting protein. The μ-homology domain (μHD) of FCHO2 binds directly to DPF sequences in Dab2 that also bind AP2. Disrupting the Dab2-FCHO2 interaction inhibited Dab2-mediated LDLR endocytosis in AP2-depleted cells. Depleting FCHO2 reduced the number but increased the size of clathrin structures on the adherent surface of HeLa cells and inhibited LDLR and transferrin receptor clustering. However, LDLR was internalized efficiently by FCHO2-deficient cells when additional time was provided for LDLR to enter the enlarged structures before budding, suggesting that later steps of endocytosis are normal under these conditions. These results indicate FCHO2 regulates the size of clathrin structures, and its interaction with Dab2 is needed for LDLR endocytosis under conditions of low AP2.