Extracellular Matrix Networks: From Connections to Functions

Abstract

The extracellular matrix (ECM) forms of a three dimensional interaction network mostly comprised of proteins, collagens being the most abundant ones (Ricard-Blum, Cold Spring Harb Perspect Biol 3:a004978, 2011), glycosaminoglycans (GAGs) and proteoglycans (PGs) (Iozzo and Schaefer, Matrix Biol 42:11–55, 2015; Karamanos et al., Chem Rev 118:9152–9232, 2018). We review here the major methods used to identify and characterize ECM protein, glycosaminoglycan, and proteoglycan interactions with a focus on high-throughput methods able to identify a number of interactions simultaneously such as yeast two hybrid assays, ECM protein and GAG arrays, and affinity purification coupled to mass spectrometry (MS). The use of large experimental interaction datasets publicly available, and of interaction databases to retrieve interaction data required to build interaction networks is discussed. The interest of the data generated from the functional and structural analyses of interactomes to decipher molecular mechanisms of biological processes, to design further functional experiments, and to select ECM proteins or GAGs and/or their biomolecular interactions as therapeutic targets is illustrated by several examples. The ultimate goal of these studies is to build three-dimensional ECM networks, integrating the 3D structure of individual ECM molecules and their complexes.