The extracellular matrix: complex interactions in health and disease

Lead Research Organisation: University of Oxford
Department Name: Obstetrics and Gynaecology

Abstract

Our research will focus on an important group of molecules that surround the cells and control their behaviour. These molecules are known collectively as the extracellular matrix, which is a complex mixture of sticky proteins. Molecules in the extracellular matrix interact with each other forming a scaffold to support the cell so that it can carry out its function. Extracellular matrix molecules also interact with cells. The cells stick to the surrounding matrix proteins using receptors on the cell surface, known as integrins. There are many types of integrin molecules which select different extracellular matrix proteins for binding. On binding to these proteins, integrins send signals to the inside of the cell. These signals change the behaviour of the cell causing it to, for example, divide or invade.

Interactions between extracellular matrix molecules and integrins are critical for maintaining the normal function of the tissue as a whole. Sometimes these interactions go wrong and this can be a major contributory factor to the cause of many different diseases. In order to prevent or promote certain interactions occurring, we need to understand exactly how the molecules fit together so that new drugs can be designed to specifically block or bolster the action of the molecules in question. Unfortunately we know very little about how these molecules interact and how cells respond to each different interaction. We aim to examine these ?molecular jigsaws? in detail by looking at the shape and behaviour of the molecules as they interact with each other, and analysing how the cell responds to the signals generated by these contacts.

Our proposed programme of research involves a multidisciplinary approach involving clinical, physiological, cellular and molecular expertise. Our discoveries will have future implications for the design of therapies for many different diseases.

Technical Summary

The extracellular matrix (ECM) has an essential function in tissue development and homeostasis. Its signalling properties are mediated by complex macromolecular interactions between different ECM components, and between ECM ligands and the integrin family of cell surface receptors. Many ECM ligands bind to integrins via a common, RGD-containing, amino acid recognition motif. Each ligand binds to a specific integrin or a number of different integrins, some of which are common receptors for diverse ligands. The molecular basis of, and the specific downstream biological events resulting from, these interactions are yet to be fully determined.

The nature of protein-protein interactions in the ECM remains a challenging area of research, since many of the ECM components have proved refractory to classical methods of study. The aim of the proposed research programme is the structural and functional characterization of such interactions at the detailed molecular level. The formation of this interdisciplinary Cooperative has brought together a powerful combination of structural, biochemical, and cellular biology expertise that is required to achieve this. A range of structural methodologies, nuclear magnetic resonance spectroscopy (NMR), X-ray crystallography and electron cryo-microscopy, will be applied. New high throughput protein expression and nanolitre scale crystallization technology will feed into these studies. The structures and functional consequences of three types of molecular complexes will be determined: i) receptor-ligand interactions of heterodimeric ectodomains of integrins avb3, avb5, a5b1, avb6 and a4b1 and different RGD-containing ECM ligands, ii) structure-function analyses of the integrin-like semaphorins and their ligands, and iii) inter-molecular interactions of ECM components.

This programme will build upon the collective strategy for cell-matrix research in Oxford that we have established during the tenure of the current Cooperative. We have identified a number of additional targets, which, although ambitious, are nevertheless realistic because of the recent advances in the platform technologies that will underpin this research. The proposed pooling of expertise and resources maximises the efficiency of projects within the Cooperative. Synergy will be facilitated by the use of central resources and infrastructure already in place in the members? Departments, at The Oxford Protein Production Facility (OPPF, supported by the MRC) and the Oxford Centre for Molecular Science (OCMS, supported by the BBSRC and EPSRC).

Publications

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Jovanovic J (2008) Fibrillin-integrin interactions in health and disease. in Biochemical Society transactions

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Loeys BL (2010) Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. in Science translational medicine