Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.

Dynamic and disordered regions in native proteins are often critical for their function, particularly in ligand binding and signaling. In certain proteins, however, such regions can contribute to misfolding and pathologic deposition as amyloid fibrils in vivo. For example, dynamic and disordered regions can promote amyloid formation by destabilizing the native structure, by directly triggering the aggregation, by promoting protein condensation, or by acting as sites of early proteolytic cleavage that favor a release of aggregation-prone fragments or facilitate fibril maturation. At the same time, enhanced dynamics in the native protein state accelerates proteolytic degradation that counteracts amyloid accumulation in vivo. Therefore, the functional need for dynamic protein regions must be balanced against their inherently labile nature. How exactly this balance is achieved and how is it shifted upon amyloidogenic mutations or post-translational modifications? To illustrate possible scenarios, here we review the beneficial and pathologic roles of dynamic and disordered regions in the native states of three families of human plasma proteins that form amyloid precursors in systemic amyloidoses: immunoglobulin light chain, apolipoproteins, and serum amyloid A. Analysis of structure, stability and local dynamics of these diverse proteins and their amyloidogenic variants exemplifies how disordered/dynamic regions can provide a functional advantage as well as an Achilles heel in pathologic amyloid formation.