Nanoscale Structural and Functional Impacts of Disease-Associated Collagen Mutations

Collagen is the most abundant structural protein in the human body, and its supramolecular organization is central to tissue mechanics and cell matrix interactions. Integrins, key mediators of these interactions, are essential for key biological processes including adhesion, migration, differentiation, and platelet aggregation. While mutations in collagen are known to cause connective tissue disorders such as Osteogenesis Imperfecta (OI) with phenotypes ranging from mild to perinatal lethal, how these mutations alter fibril level architecture, dynamics and integrin-mediated interactions remains poorly understood. Here, we generated collagen-rich extra-cellular matrix (ECM) from primary dermal fibroblasts of a healthy donor (WT) and from two OI patients carrying distinct glycine mutations: G610C, associated with moderate disease, and G907D, linked to perinatal lethality. Comparative biophysical studies reveal that both mutants retain the canonical D-banding of collagen I fibrils but differ markedly at the nanoscale. G907D fibrils exhibit greater local structural perturbations and increased molecular mobility relative to the non-lethal G610C. Importantly, integrin binding also diverges between mutants: G610C displays reduced affinity, whereas G907D exhibits enhanced affinity compared to WT. Together, these findings establish a mechanistic link between single-residue mutations, nanoscale fibril architecture and collagen-receptor interactions, and highlight how genetic or acquired collagen defects can drive ECM dysregulation.