Regulation and substrate binding of the tolloid proteinase family

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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.