Collagen I weakly interacts with the β-sheets of β2-microglobulin and enhances conformational exchange to induce amyloid formation

Amyloidogenesis is significant in both protein function and pathology. Amyloid formation of folded, globular proteins is commonly initiated by partial unfolding. However, how this unfolding event is triggered for proteins that are otherwise stable in their native environments is not well understood. The accumulation of the immunoglobulin protein {beta}2-microglobulin ({beta}2m) into amyloid plaques in the joints of long-term hemodialysis patients is the hallmark of Dialysis Related Amyloidosis (DRA). While {beta}2m does not form amyloid unassisted near neutral pH in vitro, the localization of {beta}2m deposits to joint spaces suggests a role for the local extracellular matrix (ECM) proteins, specifically collagens, in promoting amyloid formation. Indeed, collagen and other ECM components have been observed to facilitate {beta}2m amyloid formation, but the large size and anisotropy of the complex, combined with the low affinity of these interactions, has limited atomic-level elucidation of the amyloid-promoting mechanism by these molecules. Using solution NMR approaches that uniquely probe weak interactions and large complexes, we are able to derive binding interfaces for collagen I on {beta}2m and detect collagen I-induced {micro}s-ms timescale dynamics in the {beta}2m backbone. By combining solution NMR relaxation methods and 15N-dark state exchange saturation transfer experiments, we propose a model in which weak, multimodal collagen I-{beta}2m interactions promote exchange with a minor population of an amyloid-competent species to induce fibrillogenesis. The results portray the intimate role of the environment in switching an innocuous protein into an amyloid-competent state, rationalizing the localization of amyloid deposits in DRA.