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首页> 外文期刊>Computational and Structural Biotechnology Journal >A combined evolutionary and structural approach to disclose the primary structural determinants essential for proneurotrophins biological functions
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A combined evolutionary and structural approach to disclose the primary structural determinants essential for proneurotrophins biological functions

机译：一种综合的进化和结构方法，公开了易患易患型生物功能的主要结构决定因子

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The neurotrophins, i.e., Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin 3 (NT3) and Neurotrophin 4 (NT4), are known to play a range of crucial functions in the developing and adult peripheral and central nervous systems. Initially synthesized as precursors, i.e., proneurotrophins (proNTs), that are cleaved to release C-terminal mature forms, they act through two types of receptors, the specific Trk receptors (Tropomyosin-related kinases) and the pan-neurotrophin receptor p75NTR, to initiate survival and differentiative responses. Recently, all the proNTs but proNT4 have been demonstrated to be not just inactive precursors, but signaling ligands that mediate opposing actions in fundamental aspects of the nervous system with respect to the mature counterparts through dual-receptor complexes formation with a member of the VPS10 family and p75NTR. Despite the functional relevance, the molecular determinants underpinning the interactions between the pro-domains and their receptors are still elusive probably due to their intrinsically disordered nature. Here we present an evolutionary approach coupled to an experimental study aiming to uncover the structural and dynamical basis of the biological function displayed by proNGF, proBDNF and proNT3 but missing in proNT4. A bioinformatic analysis allowed to elucidate the functional adaptability of the proNTs family in vertebrates, identifying conserved key structural features. The combined biochemical and SAXS experiments shed lights on the structure and dynamic behavior of the human proNTs in solution, giving insights on the evolutionary conserved structural motifs, essential for the multifaceted roles of proNTs in physiological as well as in pathological contexts.
机译：已知神经营养素，即神经生长因子（NGF），脑衍生的神经营养因子（BDNF），神经营养蛋白3（NT3）和神经营养蛋白4（NT4）在显影和成人周围和中枢发挥着一系列至关重要的功能神经系统。最初合成为前体，即易于释放到释放C末端成熟形式的易肺泌菌素（垂直），它们通过两种类型的受体，特异性Trk受体（冠状阴素相关激酶）和Pan-Neurootrophin受体P75NTR来作用。开始生存和不同的反应。最近，所有的底头但Pront4已经证明不仅是非惰性前体，而是信号配体，但是通过与VPS10家族成员形成的双受体复合物形成成熟对应的成熟对应物中的对立动作的信号配体。和p75ntr。尽管有功能相关性，但由于其本质上无序的性质，仍然难以忽视仍然难以实现的。在这里，我们提出了一种耦合到一个实验研究的进化方法，其旨在揭示Prongf，Probdnf和Pront3所显示的生物学功能的结构和动态基础，但在Pront4中缺失。生物信息分析允许阐明脊椎动物中底族的功能适应性，识别保守的关键结构特征。结合的生化和萨克斯实验揭示了溶液中人类垂直的结构和动态行为的亮起，对进化保守的结构基序有所了解，对于生理学以及病理背景下的多方面的角色是必不可少的作用。

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