Regulation and substrate binding of the tolloid proteinase family

在哺乳动物生物学的两个基本过程中，脂质蛋白家族起着至关重要的作用。第一个是组织组装，例如骨骼生长，其中tolloid切割蛋白质前体启动组装过程。脂样蛋白移除胶原蛋白分子末端的一个区域，这种移除开始了胶原蛋白原纤维的组装过程，这对骨骼生长和其他正常健康组织的形成至关重要。其次，脂质释放储存的“生长因子”，这是一种信使分子，可以指导细胞内的过程，例如告诉细胞应该生长多少，甚至告诉细胞应该生存还是死亡。这些过程对于维持正常的组织结构和功能以及早期胚胎发育的基本过程至关重要。我们最近确定了在人类中发现的一种脂质家族成员的形状和排列，并表明这种脂质是一对的。这种自我相互作用实际上减缓了脂质的速度，可能代表了一种新的内部调节方法。脂类也可以通过蛋白质增强剂来控制，增强它们切割底物的能力（即它们的活性）。目前尚不清楚脂质如何与它们切割的许多不同分子相互作用，迫切需要深入了解这些过程，以便了解它们如何控制人类生物学中的这些不同功能。因此，我们工作的主要目的是解决tolloid的作用机制，我们相信这将导致了解它们的调节和相互作用如何支撑它们在组织组装和胚胎发育中的基本作用。我们将确定所有的tolloid是否成对工作，以及当tolloid与底物（例如胶原前体）结合时会发生什么，例如，它是保持成对还是单独工作。最后，我们将发现蛋白质增强剂是如何提高脂质活性的。了解骨形成之前的这些分子事件可能对英国有重大的健康和经济效益。在英国，50岁以后有1 / 2的女性和1 / 5的男性经历过骨折，预计到2020年，治疗绝经后女性骨质疏松性骨折的费用将增加到20亿英镑以上。我们的研究结果可能会对未来制药行业开发新的治疗方法来调节骨沉积感兴趣。骨质流失的有效治疗将显著改善老龄化人口的生活质量。

The tolloid family of proteins has essential roles in two fundamental processes in mammalian biology. The first is tissue assembly, for example bone growth, where tolloids cut protein precursors initiating the assembly process. Tolloids remove a region at the end of collagen molecules and this removal begins the collagen fibril assembly process which is essential for bone growth and the formation of other normal healthy tissues. Secondly, tolloids release stored 'growth factors' which are messenger molecules that can direct processes in cells, for instance telling them how much to grow or even whether they should live or die. These processes are critical for maintaining normal tissue structure and function and for essential processes in early embryonic development. We have recently determined the shape and arrangement of one member of the tolloid family that is found in humans, and shown that this tolloid works as a pair. This self-self interaction actually slows the tolloid down and may represent a novel method of internal regulation. Tolloids can also be controlled by protein enhancers that increase their capability of cutting their substrates (i.e. their activity). How tolloids interact with the many diverse molecules they cut is currently unknown, and insights into these processes are urgently needed in order to understand how they control such diverse functions in human biology. The main aim of our work therefore is to resolve the mechanism of action of tolloids which we believe will lead to an understanding of how their regulation and interactions underpin their fundamental roles in tissue assembly and embryo development. We will determine if all tolloids work in pairs and what happens when tolloids bind to their substrates, such as the collagen precursor, for example, does it remain paired or go solo. Finally, we will discover how protein enhancers work to improve the activity of tolloids. Understanding these molecular events preceding bone formation could have significant health and economic benefits to the UK. In the UK, 1 in 2 women and 1 in 5 men suffer a fracture after the age of 50 and the cost of treating all osteoporotic fractures in postmenopausal women has been predicted to increase to more than £2 billion by 2020. Our research findings could be of future interest to the pharmaceutical industry in developing novel treatments to modulate bone deposition. Effective treatment for bone loss would significantly improve the quality of life of an ageing population.