The Structure, Function and Evolution of the Extracellular Matrix: A Systems-Level Analysis

The extracellular matrix (ECM) is a three-dimensional meshwork of proteins, proteoglycans and polysaccharides imparting structure and mechanical stability to tissues. ECM dysfunction has been implicated in a number of debilitating conditions including cancer, atherosclerosis, asthma, fibrosis and arthritis. Identifying the components that comprise the ECM and understanding how they are organised within the matrix is key to uncovering its role in health and disease. This study defines a rigorous protocol for the rapid categorization of proteins comprising a biological system. Beginning with over 2000 candidate extracellular proteins, 357 core ECM genes and 524 functionally related (non-ECM) genes are identified. A network of high quality protein-protein interactions constructed from these core genes reveals the ECM is organised into biologically relevant functional modules whose components exhibit a mosaic of expression and conservation patterns. This suggests module innovations were widespread and evolved in parallel to convey tissue specific functionality on otherwise broadly expressed modules. Phylogenetic profiles of ECM proteins highlight components restricted and/or expanded in metazoans, vertebrates and mammals, indicating taxon-specific tissue innovations. Modules enriched for medical subject headings illustrate the potential for systems based analyses to predict new functional and disease associations on the basis of network topology. This study also explores the evolutionary forces that guided the development of the ECM. Analyses of domain conservation patterns in ECM proteins, including the use of a novel framework for identifying non-contiguous, conserved arrangements of domains shows most are of pre-deuterostome origin. Many participate in novel domain arrangements in vertebrates suggesting the sampling of new domain combinations was an important mechanism leading to neofunctionalization of paralogous ECM genes. Distinct types of proteins and/or the biological systems in which they operate may have influenced the types of evolutionary forces that drive protein innovation. This emphasizes the need for rigorously defined systems to address questions of evolution that focus on specific systems of interacting proteins such as the ECM. Finally, overviewing the current state of our knowledge of the ECM, this study addresses important gaps and highlights areas worthy of further investigation.Ph.D