Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5
Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5
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DOI：
10.1242/jcs.048686
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发表时间：
2009-07-15
影响因子：
4
通讯作者：
Bright, Nicholas
中科院分区：
文献类型：
--
作者：
Seaman, Matthew N. J.;Harbour, Michael E.;Bright, Nicholas
Retromer 是一种膜相关的异五聚体外壳复合物，其功能在于从内体到高尔基体修复不依赖于阳离子的 6-磷酸甘露糖受体、Wntless 蛋白和其他具有生理意义的膜蛋白。 Retromer 包含两个功能子复合体：货物选择性子复合体是 VPS35、VPS29、VPS26 蛋白的三聚体，而分选 nexin 蛋白 Snx1 和 Snx2 的功能是调节内体膜。与含有 PtdIns3P 结合 PX 结构域的分选连接蛋白不同，货物选择性 VPS35/29/26 复合物没有脂质结合结构域，并且其向内体膜的募集在机制上仍然是未知的。在本研究中，我们表明 VPS35/29/26 复合物与小 GTPase Rab7 相互作用，并且需要 Rab7 来招募内体。我们发现，导致周围神经病变（腓骨肌萎缩症）的 Rab7K157N 突变体不与 VPS35/29/26 复合物相互作用，从而导致与膜的关联减弱。我们还发现了一种新型逆转录酶相互作用蛋白 TBC1D5，它是 Rab GAP 蛋白家族的成员，可负向调节 VPS35/29/26 募集并导致 Rab7 从膜上解离。因此，我们建议货物选择性 VPS35/29/26 复合物的募集由 Rab7 催化并由 Rab-GAP 蛋白 TBC1D5 抑制。
Retromer is a membrane-associated heteropentameric coat complex that functions in the endosome-to-Golgi retrieval of the cation-independent mannose-6-phosphate receptor, the Wntless protein and other membrane proteins of physiological significance. Retromer comprises two functional subcomplexes: the cargo-selective subcomplex is a trimer of the VPS35, VPS29, VPS26 proteins, whereas the sorting nexin proteins, Snx1 and Snx2 function to tubulate the endosomal membrane. Unlike the sorting nexins, which contain PtdIns3P-binding PX domains, the cargo-selective VPS35/29/26 complex has no lipid-binding domains and its recruitment to the endosomal membrane remains mechanistically uncharacterised. In this study we show that the VPS35/29/26 complex interacts with the small GTPase Rab7 and requires Rab7 for its recruitment to the endosome. We show that the Rab7K157N mutant that causes the peripheral neuropathy, Charcot-Marie-Tooth disease, does not interact with the VPS35/29/26 complex, resulting in a weakened association with the membrane. We have also identified a novel retromer-interacting protein, TBC1D5, which is a member of the Rab GAP family of proteins that negatively regulates VPS35/29/26 recruitment and causes Rab7 to dissociate from the membrane. We therefore propose that recruitment of the cargo-selective VPS35/29/26 complex is catalysed by Rab7 and inhibited by the Rab-GAP protein, TBC1D5.