SPP 1464: Principles and Evolution of Actin-nucleator Complexes

肌动蛋白细胞骨架是整个进化过程中细胞结构的主要决定因素。在从原核生物到后生动物的细胞复杂性增加的同时，肌动蛋白细胞骨架及其调控因子的多样性也增加了。进化出特定的机制，以满足动植物王国相互作用的细胞网络的新的结构需求。尽管它具有基本的细胞生物学重要性，并在人类疾病和治疗中具有巨大的意义，但许多潜在的调节功能长期以来一直难以捉摸。直到最近，由于从基因组计划中获得了革命性的知识，越来越多的调控机制出现了，反映了肌动蛋白细丝结构和功能的多样性。肌动蛋白细丝在特定的亚细胞室由肌动蛋白单体组装而成，以响应不同的信号级联反应。由于肌动蛋白单体的稳定结合形成二聚体和三聚体(在称为成核的过程中)在热力学上是不利的，并且由于肌动蛋白单体结合蛋白的活性，在细胞中不会发生自发的肌动蛋白聚合。因此，肌动蛋白细丝的组装需要有助于克服细丝成核的这一动力学障碍的因素。直到2002年，Arp2/3复合体是唯一已知的驱动肌动蛋白成核的机制，但从那时起，对成核机制的复杂性的了解呈指数级增长，为我们今天留下了至少28种不同的哺乳动物细胞核因子。它们可分为三个主要基团，即Arp2/3复合体及其不同的成核促进因子、福尔马林和含WH2的成核剂。这一优先计划的目的是在一个跨学科网络中调查这些核因子的结构、功能、调控和相互作用，以便将成核机制的多样性与多种不同的细胞肌动蛋白结构和功能联系起来。除了细胞生物和生化分析，包括对复合体结构方面的高度重视，我们希望通过将我们对各种模式生物(细菌、真菌、植物、昆虫、哺乳动物)的肌动蛋白组织的分析与生物信息学方法相结合，获得宝贵的信息。这与人工合成肌动蛋白核子的设计以及生物物理和建模方法一起，应该为我们对肌动蛋白成核复合体的原理和进化的理解铺平道路，并将开辟将结果转化为临床应用的途径。

The actin cytoskeleton is a major determinant of cellular architecture throughout evolution. In parallel with increasing cellular complexity from prokaryotes to metazoans, the diversity of the actin cytoskeleton and its regulators increased. Specific mechanisms evolved to fulfil the novel structural demands of the interactive cellular networks of the animal and plant kingdoms. Despite its fundamental cell biological importance and its enormous implication in human diseases and therapy, many of the underlying regulatory functions have remained elusive for a long time. Only recently, in debt to the impact of the revolutionary gain of knowledge from the genome projects, an increasing number of regulatory mechanisms emerged that reflect the diversity of actin filament structures and functions. Actin filaments assemble from actin monomers at specified subcellular compartments in response to different signalling cascades. Owing to the fact that the stable association of actin monomers to form dimers and trimers (in a process termed nucleation) is thermodynamically unfavourable, and due to the activity of actin monomer binding proteins, no spontaneous actin polymerisation occurs in cells. Thus, assembly of actin filaments requires factors that help to overcome this kinetic barrier to filament nucleation. Until 2002, the Arp2/3 complex was the only machinery known to drive actin nucleation, but since then, knowledge on the complexity of nucleation mechanisms has exponentially increased, leaving us today with at least 28 different nucleators for mammalian cells. These can be divided into three principal groups, i.e. the Arp2/3 complex and its different nucleation promoting factors, formins and WH2-containing nucleators. The aim of this Priority Programme is to investigate in an interdisciplinary network the structures, the functions, the regulation and the interplay of these nucleators in order to correlate the diversity of nucleation mechanisms with the multitude of distinct cellular actin structures and functions. In addition to cell biological and biochemical assays, including a strong emphasis on structural aspects of the complexes, we expect to obtain invaluable information from a combination of our analysis of actin organisation in a wide range of model organisms (bacteria, fungi, plants, insects, mammals) with bioinformatics approaches. This, together with the design of synthetic actin nucleators as well as biophysical and modelling approaches, should pave the way to a breakthrough in our understanding of the principles and evolution of actin nucleation complexes and will open avenues to translate the results to clinical applications.