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Arhgef5 Binds α-Dystrobrevin 1 and Regulates Neuromuscular Junction Integrity.
Frontiers in Molecular Neuroscience ( IF 3.5 ) Pub Date : 2020-05-13 , DOI: 10.3389/fnmol.2020.00104
Krzysztof M Bernadzki 1 , Patrycja Daszczuk 1 , Katarzyna O Rojek 1, 2 , Marcin Pęziński 1 , Marta Gawor 1 , Bhola S Pradhan 1 , Teresa de Cicco 1 , Monika Bijata 3 , Krystian Bijata 3 , Jakub Włodarczyk 3 , Tomasz J Prószyński 1, 4 , Paweł Niewiadomski 1, 5
Affiliation  

The neuromuscular junctions (NMJs) connect muscle fibers with motor neurons and enable the coordinated contraction of skeletal muscles. The dystrophin-associated glycoprotein complex (DGC) is an essential component of the postsynaptic machinery of the NMJ and is important for the maintenance of NMJ structural integrity. To identify novel proteins that are important for NMJ organization, we performed a mass spectrometry-based screen for interactors of α-dystrobrevin 1 (aDB1), one of the components of the DGC. The guanidine nucleotide exchange factor (GEF) Arhgef5 was found to be one of the aDB1 binding partners that is recruited to Tyr-713 in a phospho-dependent manner. We show here that Arhgef5 localizes to the NMJ and that its genetic depletion in the muscle causes the fragmentation of the synapses in conditional knockout mice. Arhgef5 loss in vivo is associated with a reduction in the levels of active GTP-bound RhoA and Cdc42 GTPases, highlighting the importance of actin dynamics regulation for the maintenance of NMJ integrity.



中文翻译:

Arhgef5绑定α-Dystrobrevin1并调节神经肌肉连接完整性。

神经肌肉接头(NMJ)将肌肉纤维与运动神经元连接起来,并使骨骼肌协调收缩。肌营养不良蛋白相关糖蛋白复合物(DGC)是NMJ突触后机制的重要组成部分,对于维护NMJ结构完整性非常重要。为了鉴定对NMJ组织重要的新型蛋白质,我们对α-dystrobrevin1(aDB1)(DGC的成分之一)的相互作用子进行了基于质谱的筛选。发现胍核苷酸交换因子(GEF)Arhgef5是以磷酸依赖性方式募集到Tyr-713的aDB1结合伴侣之一。我们在这里显示Arhgef5定位于NMJ,并且其在肌肉中的遗传耗竭会导致条件基因敲除小鼠中突触的断裂。Arhgef5损失体内 这与活性GTP结合的RhoA和Cdc42 GTPases的水平降低有关,突显了肌动蛋白动力学调节对于维持NMJ完整性的重要性。

更新日期:2020-05-13
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