Mechanism, control and cellular functions of Cobl-mediated actin nucleation

复杂的肌动蛋白超结构的形成是所有真核生物生命所不可缺少的，但因此关键依赖于促进第一批肌动蛋白单体组装的因素的帮助，这一过程被称为成核。尽管形成了丰富的肌动蛋白结构，但在高等真核生物中只有两类肌动蛋白成核因子得到很好的证实，即Arp2/3复合体和福尔马林。通过COBL，我们最近发现了一种新的、非常强大的肌动蛋白核因子，它是正常神经形态发生所必需的，属于新的基于WH2结构域的核因子。我们预计，我们的全面研究不仅将使我们能够揭开COBL控制肌动蛋白细胞骨架的详细分子机制，而且还将进一步深入了解高等真核生物的不同肌动蛋白超结构是如何形成的，以及它们如何支持它们所参与的巨大多样性的细胞过程。COBL蛋白相互作用的鉴定和功能表征，可能控制这一新的强大的肌动蛋白成核机制的活性和/或亚细胞定位，将显著增加我们对神经形态发生和神经元网络形成的潜在的肌动蛋白细胞骨架过程的分子理解--这些功能对所有高等真核生物的生命至关重要。

The formation of complex actin superstructures is indispensable for life of all eukaryotes but thereby critically relies on the help of factors facilitating the assembly of the first actin monomers, a process termed nucleation. Despite the wealth of different actin structures formed, only two classes of such actin nucleation factors are well established in higher eukaryotes, the Arp2/3 complex and formins. With Cobl, we have recently identified a novel and very powerful actin nucleator indispensable for proper neuromorphogenesis that belongs to the new class of WH2 domain-based nucleators. We expect that our comprehensive studies will not only allow us to unravel the detailed molecular mechanism by which Cobl controls the actin cytoskeleton but will furthermore lead to deeper insights into how the different actin superstructures of higher eukaryotes are formed and how they support the huge diversity of cellular processes they are involved in. The identification and functional characterization of Cobl protein interactions, which may control the activity and/or the subcellular localization of this novel powerful machinery for actin nucleation, will significantly increase our molecular understanding of the actin cytoskeletal processes underlying neuromorphogenesis and the formation of neuronal networks – functions crucial for life of all higher eukaryotes.