Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt am Main, Germany; Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584CH Utrecht, the Netherlands; International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
Dev Cell. 2014 Feb 24;28(4):381-93. doi: 10.1016/j.devcel.2014.01.018.
Regulation of cargo transport via adaptor molecules is essential for neuronal development. However, the role of PDZ scaffolding proteins as adaptors in neuronal cargo trafficking is still poorly understood. Here, we show by genetic deletion in mice that the multi-PDZ domain scaffolding protein glutamate receptor interacting protein 1 (GRIP1) is required for dendrite development. We identify an interaction between GRIP1 and 14-3-3 proteins that is essential for the function of GRIP1 as an adaptor protein in dendritic cargo transport. Mechanistically, 14-3-3 binds to the kinesin-1 binding region in GRIP1 in a phospho-dependent manner and detaches GRIP1 from the kinesin-1 motor protein complex thereby regulating cargo transport. A single point mutation in the Thr956 of GRIP1 in transgenic mice impairs dendritic development. Together, our results show a regulatory role for GRIP1 during microtubule-based transport and suggest a crucial function for 14-3-3 proteins in controlling kinesin-1 motor attachment during neuronal development.
衔接蛋白调节货物运输对神经元发育至关重要。然而，PDZ 支架蛋白作为神经元货物运输中的衔接蛋白的作用仍知之甚少。在这里，我们通过在小鼠中的基因缺失表明，多 PDZ 结构域支架蛋白谷氨酸受体相互作用蛋白 1（GRIP1）是树突发育所必需的。我们确定了 GRIP1 与 14-3-3 蛋白之间的相互作用，这对于 GRIP1 作为树突货物运输中的衔接蛋白的功能至关重要。在机制上，14-3-3 以磷酸依赖性方式结合到 GRIP1 中的驱动蛋白-1 结合区域，并将 GRIP1 从驱动蛋白-1 马达蛋白复合物上脱离下来，从而调节货物运输。在转基因小鼠中，GRIP1 的 Thr956 单点突变会损害树突的发育。总之，我们的结果表明，GRIP1 在基于微管的运输过程中起调节作用，并表明 14-3-3 蛋白在控制神经元发育过程中驱动蛋白-1 马达附着方面具有关键功能。
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