Regulation and substrate binding of the tolloid proteinase family

Tolloid 蛋白酶家族的调节和底物结合

• 批准号: BB/I012265/1
• 负责人: Clair Baldock
• 金额: $ 41.45万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI012265%2F1
• 关键词: Regulation; substrate; binding; tolloid; proteinase

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.

tolloid蛋白家族在哺乳动物生物学的两个基本过程中具有重要作用。第一个是组织组装，例如骨骼生长，其中tolloids切割蛋白质前体，启动组装过程。Tolloids去除了胶原分子末端的区域，这种去除开始了胶原原纤维组装过程，这对骨生长和其他正常健康组织的形成至关重要。其次，tolloids释放出储存的“生长因子”，它们是可以指导细胞过程的信使分子，例如告诉它们生长多少，甚至是它们应该生存还是死亡。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tolloid家族的一个成员的形状和排列，并表明这个tolloid是一对。这种自我与自我的相互作用实际上减缓了tolloid的速度，可能代表了一种新的内部调节方法。Tolloids也可以通过蛋白增强剂来控制，所述蛋白增强剂增加其切割其底物的能力（即其活性）。tolloids如何与它们切割的许多不同分子相互作用目前尚不清楚，迫切需要深入了解这些过程，以了解它们如何控制人类生物学中的各种功能。因此，我们工作的主要目的是解决tolloids的作用机制，我们相信这将有助于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。我们将确定是否所有的tolloids都是成对工作的，以及当tolloids与它们的底物结合时会发生什么，例如胶原蛋白前体，它是保持配对还是单独工作。最后，我们将发现蛋白增强剂如何提高tolloids的活性。了解骨形成前的这些分子事件可能对英国产生重大的健康和经济效益。在英国，1/2的女性和1/5的男性在50岁后发生骨折，预计到2020年，治疗绝经后女性所有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是未来的兴趣，制药行业在开发新的治疗方法来调节骨沉积。有效治疗骨质流失将显著改善老龄人口的生活质量。

项目成果

Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation.

• DOI: 10.7554/elife.05508
• 发表时间: 2015-02-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Winstanley J;Sawala A;Baldock C;Ashe HL
• 通讯作者: Ashe HL

Heterogeneity of Collagen VI Microfibrils

VI 型胶原微纤维的异质性

• DOI: 10.3204/pubdb-2016-04625
• 发表时间: 2016
• 作者: Maaß T

Heterogeneity of Collagen VI Microfibrils: STRUCTURAL ANALYSIS OF NON-COLLAGENOUS REGIONS.

• DOI: 10.1074/jbc.m115.705160
• 发表时间: 2016-03-04
• 期刊: The Journal of biological chemistry
• 作者: Maaß T;Bayley CP;Mörgelin M;Lettmann S;Bonaldo P;Paulsson M;Baldock C;Wagener R
• 通讯作者: Wagener R

Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway.

扭曲胃结构的结构表征为BMP信号通路上相对功能提供了见解。

• DOI: 10.1016/j.matbio.2016.01.019
• 发表时间: 2016-09
• 期刊: MATRIX BIOLOGY
• 影响因子: 6.9
• 作者: Troilo, Helen;Barrett, Anne L.;Zuk, Alexandra V.;Lockhart-Cairns, Michael P.;Wohl, Alexander P.;Bayley, Christopher P.;Dajani, Rana;Tunnicliffe, Richard B.;Green, Lewis;Jowitt, Thomas A.;Sengle, Gerhard;Baldock, Clair
• 通讯作者: Baldock, Clair

The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity.

• DOI: 10.1042/bst20150071
• 发表时间: 2015-10
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Troilo H;Barrett AL;Wohl AP;Jowitt TA;Collins RF;Bayley CP;Zuk AV;Sengle G;Baldock C
• 通讯作者: Baldock C