Protein arginine methylation by PRMT2 – a putative versatile posttranslational regulatory mechanism for controlling actin nucleation underlying proper neuromorphogenesis

PRMT2 引起的蛋白质精氨酸甲基化——一种假定的多功能翻译后调节机制，用于控制适当神经形态发生下的肌动蛋白成核

• 批准号: 468911204
• 负责人: Professorin Dr. Britta Qualmann
• 金额: --
• 依托单位: Institut für Biochemie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/468911204?language=en
• 关键词: Protein; arginine; methylation; PRMT2; putative

The brain encompasses a sophisticated network of neuronal cells with extremely elaborated morphologies of their signal-sending (axonal) and –receiving (dendritic) compartments. De novo actin filament formation is one of the major driving and steering forces for the development and plasticity of the neuronal arbor. Actin filament assembly thus requires tight temporal and spatial control. Such control is most effective at the level of regulating actin nucleation promoting factors, as these are key components for filament formation. Our recent results unveiled that Cobl, an actin nucleator critical for shaping the dendritic arbor of neuronal cells, is controlled by arginine methylation. This was unexpected, as arginine methylation is a posttranslational modification previously known to predominantly control nuclear processes. The protein arginine methyltransferase PRMT2 was identified to associate with Cobl and regulate its cytoskeletal properties. Importantly, we found that PRMT2 also was critical for dendritic arborization and that its crucial role required its enzymatic activity and a protein interaction domain unique for this protein arginine methyltransferase. The identification of additional highly brain-enriched actin nucleation promoting factors as further interaction partners of PRMT2 in our mass spectrometry screen now led to the exciting working hypothesis that arginine methylation may be a more general and versatile mean for controlling neuronal network formation and proper brain function. We therefore here propose to investigate whether PRMT2 is also responsible for posttranslational modification of an additional actin nucleation promoting factor implicated in neuromorphogenesis found in our mass spectrometry screen. Subsequent studies aim at unveiling the molecular mechanistic consequences of PRMT2-mediated arginine methylation of this important actin cytoskeletal component on its cytoskeletal properties and its regulatory protein network interactions. Functional studies in neurons will be conducted in order to uncover a putative generalized function of PRMT2-mediated arginine methylation in dendritic arborization mediated by actin nucleation promoting factors.Further important aspects in neuronal network formation are axonal development and the establishment of pre- and postsynaptic specializations subsequent to neurite induction and branching. Since also the induction and plasticity of these specialized morphological compartments of neurons have been demonstrated to be highly dependent on actin organization and dynamics, we propose to unveil whether and to what extent the function of PRMT2 in neuronal morphology control reaches beyond dendritic arborization.Together, this work will provide important insights into regulatory posttranslational mechanisms targeting actin nucleation-promoting factors crucial for neuromorphogenesis and thereby shed light on a key process for the formation of neuronal networks in vertebrate brains.

大脑包含一个复杂的神经细胞网络，具有极其精细的信号发送(轴突)和接收(树突)间隔的形态。新生肌动蛋白微丝的形成是神经元突起发育和可塑性的主要驱动力和导向力量之一。因此，肌动蛋白细丝组装需要严格的时间和空间控制。这种控制在调节肌动蛋白成核促进因子的水平上最为有效，因为这些因子是细丝形成的关键成分。我们最近的研究结果揭示，COBL是一种肌动蛋白核因子，对形成神经细胞的树突状突起至关重要，它受精氨酸甲基化控制。这是意想不到的，因为精氨酸甲基化是一种翻译后修饰，以前已知主要控制核过程。精氨酸甲基转移酶PRMT2蛋白被鉴定为与COBL相关并调节其细胞骨架特性。重要的是，我们发现PRMT2对于树突状分支也是关键的，它的关键作用需要它的酶活性和该蛋白精氨酸甲基转移酶所特有的蛋白相互作用结构域。在我们的质谱学筛选中，额外的高度脑丰富的肌动蛋白成核促进因子被确定为PRMT2的进一步相互作用伙伴，现在导致了令人兴奋的工作假说，精氨酸甲基化可能是控制神经元网络形成和正常大脑功能的更通用和通用的手段。因此，我们建议调查PRMT2是否也对在我们的质谱学筛查中发现的与神经形态发生有关的另一种肌动蛋白成核促进因子的翻译后修饰负责。后续研究旨在揭示PrMT2介导的精氨酸甲基化这一重要的肌动蛋白细胞骨架成分对其细胞骨架特性及其调控蛋白网络相互作用的分子机制后果。神经元的功能研究将被用来揭示PrMT2介导的精氨酸甲基化在肌动蛋白成核促进因子介导的树突树枝形成中的普遍功能。进一步的神经元网络形成的重要方面是轴突的发育以及突触诱导和分支后突触前和突触后的特化的建立。由于这些神经元的特殊形态区段的诱导和可塑性也被证明高度依赖于肌动蛋白的组织和动力学，我们建议揭示PRMT2在神经元形态控制中的功能是否以及在多大程度上超出了树突树枝状结构。总之，这项工作将为针对对神经形态发生至关重要的肌动蛋白成核促进因子的翻译后调控机制提供重要的见解，从而阐明脊椎动物大脑中神经网络形成的关键过程。