Mechanisms of kinesin control by kinesin binding protein

在我们所有的细胞中，被称为运动蛋白的分子马达一样的机器沿着被称为微管的细丝行走，以便根据需要将货物运送到亚区域。此外，动蛋白可以重组微管本身的排列和长度。这些动蛋白功能在细胞分裂和建立专门的动物细胞的复杂的、区隔的性质方面特别重要。在细胞分裂过程中，动蛋白对于产生驱散遗传物质所需的力量和微管排列至关重要。在细胞发育和专门化方面，Kinesins重新排列微管支架，并确保小室组件按需交付。事实上，肌动蛋白在我们身体的大多数工作中都是基本的，包括意识、学习和记忆背后的神经细胞的维持和重塑。因此，考虑到它们的重要功能，运动蛋白活性的异常与许多疾病有关，从癌症到痴呆。为了在指定的细胞亚域和所需的时间协调特定运动蛋白马达的活动，细胞采用了许多运动蛋白控制机制。一种令人兴奋的运动蛋白调节因子，称为运动蛋白结合蛋白(KBP)，已被证明可以防止特定亚型运动蛋白的微管附着和运动。基于KBP的运动蛋白调控涉及到越来越多的领域，包括大脑和心脏发育、细胞分裂、神经细胞功能和精子构建。KBP功能的改变已被证明会导致一种被称为Goldberg-Shprint tzen综合征的衰弱的神经发育状况，以及降低神经母细胞瘤的存活率，神经母细胞瘤是一种儿童癌症。鉴于KBP及其激动素靶标的重要性，人们对KBP知之甚少。了解KBP如何阻止运动蛋白的微管附着和运动，它如何选择特定的运动蛋白亚型，以及KBP本身的行为如何受到控制，这是至关重要的。拟议的项目旨在使用诺贝尔奖获得者冷冻电子显微镜的尖端技术来获取KBP与Kinesin和监管伙伴相互作用的详细3D架构描述，以回答这些问题。低温电子显微镜可以用来研究分子机器在接近自然的条件下的动态结构，利用电子对光的增强分辨率来获得无与伦比的细节。这项技术最近经历了一场技术和理论革命，使常规的原子级分子细节得以实现，从而产生了独特的发现。除了加强我们对动蛋白和基于KBP的生物过程的理解外，更好地描述KBP将有助于描述它在动蛋白和KBP相关疾病中的作用，可能会导致新的治疗方法。

In all our cells molecular motor-like machines known as kinesins walk along filaments called microtubules in order to deliver cargos to subregions upon demand. Furthermore, kinesins can reorganise the arrangement and length of microtubules themselves. These kinesin functions are particularly important in cell division and in establishing the complex, compartmentalised nature of specialised animal cells. During cell division kinesins are vital for creating the forces and microtubule arrangements required to drive genetic material apart. In cellular development and specialisation kinesins rearrange the microtubule scaffolding and make sure subcompartment components are delivered upon demand. In fact, kinesins are fundamental in most of our body's workings, including the maintenance and remodelling of nerve cells behind consciousness, learning and memory. Accordingly given their vital functions, abnormalities in kinesin activity are implicated in a number of illnesses, from cancer to dementia.In order to orchestrate the activity of particular kinesin motors in designated cellular subdomains and at required times, cells have employed a number of kinesin control mechanisms. An exciting kinesin regulator, known as kinesin-binding protein (KBP) has been shown to prevent microtubule attachment and movement of specific subtypes of kinesins. KBP-based regulation of kinesins is being implicated in an expanding list of areas, including brain and heart development, cell division, nerve cell functioning and sperm construction. Altered KBP function has been shown to cause a debilitating neurodevelopmental condition known as Goldberg-Shprintzen syndrome, as well as decrease survival rates in neuroblastoma, a childhood cancer. Given the importance of KBP and its kinesin targets, KBP is poorly understood. It is crucial to understand how KBP prevents the microtubule attachment and motility of kinesins, how it selects particular kinesin subtypes and how the actions of KBP itself are controlled. The proposed project aims to use the cutting-edge Nobel prize winning technique of cryo-electron microscopy to acquire detailed 3D architectural descriptions of KBP interactions with kinesins and regulatory partners, in order to answer these questions. Cryo-electron microscopy can be used to study the dynamic structures of molecular machines in near-native conditions, using the enhanced resolving power of electrons over light for unrivalled detail. The technique has undergone a recent technological and theoretical revolution, enabling routine atomic-level molecular detail leading to unique discoveries. Apart from enhancing our understanding of kinesin and KBP-based biological processes, a better characterisation of KBP will help describe its role in kinesin and KBP-associated illnesses, potentially leading to new therapeutics.