Molecular mechanistic properties of a novel N-Ank superfamily member, Ankrd24, its functions and its interplay with BAR domain proteins in modulating membranes topologies and shaping cells

新型 N-Ank 超家族成员 Ankrd24 的分子机制特性、其功能及其与 BAR 结构域蛋白在调节膜拓扑和塑造细胞中的相互作用

• 批准号: 500745644
• 负责人: Privatdozent Dr. Michael Manfred Kessels
• 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/500745644?language=en
• 关键词: Molecular; mechanistic; properties; novel; Ank

Shaping membranes is crucial for establishing, maintaining and changing the morphology of cellular organelles and of entire cells. Proteins that can directly power the required local membrane topology changes thus attract high interest. Ankyrin repeats adopt a curved structure and are one of the most frequently observed structural features in proteins. We recently proposed that, mainly based on the exemplary examination of ankycorbin, a newly discovered subset of ankyrin repeat proteins, which we termed N-Ank proteins, uses a combination of an amphipathic α-helix and ankyrin repeats to sense membrane curvature and to shape membranes. We here propose to characterize a thus far merely predicted member of this novel superfamily, Ankrd24, as putative membrane shaper, to identify its functions in shaping the dendritic arbor of neurons during their development, to address its molecular and functional interplay with members of the BAR domain protein family of membrane shapers and to unveil the molecular mechanisms Ankrd24 uses for its functions by comprehensive biochemical studies, (ultra-)high-resolution imaging and functional analyses. Detailed characterizations of the molecular mechanistic properties and cell biological functions of Ankrd24 will reveal the fundamental principles Ankrd24 uses to interact with and modulate the topology of membranes. Analyses of Ankrd24 splice variants that affect the N-Ank module will give important insights into the functional consequences of Ankrd24’s alternative splicing in particular and into how to modulate N-Ank module properties in general.Our identification of an interaction of Ankrd24 with another, distinct protein family of membrane shapers furthermore serves as exciting starting point to examine whether and to what extent different membrane topology-recognizing and -modulating proteins cooperate in shaping membranes and entire cells. We will thus address this novel concept by comprehensive biochemical analyses as well as by high-resolution imaging and functional studies in neurons. In summary, studying the mechanisms and the functional role of a putative, novel N-Ank superfamily member in neuromorphogenesis and examining its physical and functional interaction with another membrane shaper of distinct nature will open an important new chapter in our understanding of the morphogenesis of cellular membranes and of entire cells.

膜的成形对于建立、维持和改变细胞器和整个细胞的形态至关重要。因此，可以直接为所需的局部膜拓扑结构变化提供动力的蛋白质吸引了很高的兴趣。锚蛋白重复序列采用弯曲结构，是蛋白质中最常见的结构特征之一。我们最近提出，主要是基于ankycorbin的示例性检查，一个新发现的锚蛋白重复序列蛋白的子集，我们称之为N-Ank蛋白，使用两亲性α-螺旋和锚蛋白重复序列的组合来感测膜曲率和塑造膜。我们在这里提出了表征这个新的超家族的一个迄今为止仅仅预测的成员，Ankrd 24，作为假定的膜成形剂，以确定其在神经元发育过程中形成树突状乔木的功能，以解决其与膜成形剂的BAR结构域蛋白家族成员的分子和功能相互作用，并通过全面的生物化学研究揭示Ankrd 24用于其功能的分子机制，（超）高分辨率成像和功能分析。Ankrd 24的分子机械特性和细胞生物学功能的详细表征将揭示Ankrd 24用于与膜相互作用和调节膜拓扑结构的基本原理。对影响N-Ank模块的Ankrd 24剪接变体的分析将对特别是Ankrd 24的选择性剪接的功能后果以及如何调节N-Ank模块特性提供重要的见解。此外，膜成形剂的不同蛋白质家族作为令人兴奋的起点，以检查不同的膜拓扑结构是否以及在多大程度上，识别和调节蛋白质在形成膜和整个细胞中合作。因此，我们将通过全面的生化分析以及神经元的高分辨率成像和功能研究来解决这个新概念。总之，研究一个假定的，新的N-Ank超家族成员在神经形态发生中的机制和功能作用，并研究其与另一种不同性质的膜成形剂的物理和功能相互作用，将为我们理解细胞膜和整个细胞的形态发生开辟一个重要的新篇章。