Mapping Structural Landmarks, Ligand Binding Sites, and Missense Mutations to the Collagen IV Heterotrimers Predicts Major Functional Domains, Novel Interactions, and Variation in Phenotypes in Inherited Diseases Affecting Basement Membranes

ABSTRACT: Collagen IV is the major protein found in basement membranes. It comprises three heterotrimers (a1a1a2, a3a4a5, and a5a5a6) that form distinct networks, and are responsible for membrane strength and integrity. We constructed linear maps of the collagen IV heterotrimers (‘‘interactomes’’) that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype–phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin, and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and diseas