Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo
Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo
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DOI：
10.1038/nchembio.686
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发表时间：
2011-12-01
影响因子：
14.8
通讯作者：
Wittinghofer, Alfred
中科院分区：
文献类型：
--
作者：
Ismail, Shehab A.;Chen, Yong-Xiang;Wittinghofer, Alfred
脂化的Rho和Rab GTP结合蛋白与称为“鸟嘌呤核苷酸解离抑制剂”（GDI）的增溶因子复合在膜之间转运。已提出使用GDI位移因子（GDF）从GDI卸载，但在机械上仍然难以捉摸。PDE δ是几种异戊二烯化Ras亚家族蛋白质的推定增溶因子。在这里，我们报告了完全修饰的法尼基化Rheb-GDP与PDE δ复合的结构。该结构解释了Rheb与PDE δ的核苷酸非依赖性结合以及PDE δ的松弛特异性。我们证明，G蛋白Arl 2和Arl 3作为法尼基化货物的变构释放因子以GTP依赖的方式起作用。因此，我们描述了一个新的运输系统法尼基化的G蛋白，涉及一个GDI样分子和明确的GDF。考虑到PDE δ对于适当的Ras和Rheb信号传导的重要性，这项研究有助于开发抗癌治疗的新靶点。
Lipidated Rho and Rab GTP-binding proteins are transported between membranes in complex with solubilizing factors called 'guanine nucleotide dissociation inhibitors' (GDIs). Unloading from GDIs using GDI displacement factors (GDFs) has been proposed but remains mechanistically elusive. PDE delta is a putative solubilizing factor for several prenylated Ras-subfamily proteins. Here we report the structure of fully modified farnesylated Rheb-GDP in complex with PDE delta. The structure explains the nucleotide-independent binding of Rheb to PDE delta and the relaxed specificity of PDE delta. We demonstrate that the G proteins Arl2 and Arl3 act in a GTP-dependent manner as allosteric release factors for farnesylated cargo. We thus describe a new transport system for farnesylated G proteins involving a GDI-like molecule and an unequivocal GDF. Considering the importance of PDE delta for proper Ras and Rheb signaling, this study is instrumental in developing a new target for anticancer therapy.