Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 Utrecht, the Netherlands.
Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands.
Cell Rep. 2018 Jul 17;24(3):685-700. doi: 10.1016/j.celrep.2018.06.071.
Tight regulation of neuronal transport allows for cargo binding and release at specific cellular locations. The mechanisms by which motor proteins are loaded on vesicles and how cargoes are captured at appropriate sites remain unclear. To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines. Furthermore, we found that specific TANC2 mutations-reported in patients with different neuropsychiatric disorders-abolish the interaction with KIF1A. We propose a model in which Ca/CaM regulates cargo binding and liprin-α and TANC2 recruit KIF1A-transported vesicles.
神经元运输的紧密调控允许货物在特定的细胞位置结合和释放。目前尚不清楚马达蛋白如何装载在囊泡上，以及货物如何在适当的部位被捕获。为了更好地理解 KIF1A 驱动的致密核心囊泡 (DCV) 运输是如何被调控的，我们鉴定了 KIF1A 的相互作用组，并关注了三个结合伙伴：钙结合蛋白钙调蛋白 (CaM) 和两个突触支架蛋白：liprin-α 和 TANC2。我们发现，钙通过 CaM 作用增强了 KIF1A 与 DCV 的结合，并增加了囊泡的运动性。相比之下，liprin-α 和 TANC2 不是 KIF1A 货物复合物的一部分，但它们在树突棘上捕获 DCV。此外，我们发现特定的 TANC2 突变-在患有不同神经精神疾病的患者中报道-消除了与 KIF1A 的相互作用。我们提出了一个模型，其中 Ca/CaM 调节货物结合，liprin-α 和 TANC2 招募 KIF1A 运输的囊泡。
