Abstract
Light-chain amyloidosis (AL) is the most common systemic amyloidosis and is caused by the deposition of mainly insoluble immunoglobulin light chain amyloid fibrils in multiple organs, causing organ failure and eventually death. The germ-line λ6a has been implicated in AL, where a single point mutant at amino acid 24 (6aJL2-R24G) has been observed in around 25% of patient samples. Structural analysis has shown only subtle differences between both proteins; nevertheless, 6aJL2-R24G is more prone to form amyloid fibrils. To improve our understanding of the role of protein flexibility in amyloid fibril formation, we have used a combination of solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations to complement the structural insight with dynamic knowledge. Fast timescale dynamics (ps–ns) were equivalent for both proteins, but suggested exchange events for some residues. Even though most of the intermediate dynamics (μs–ms) occurred at a similar region for both proteins, the specific characteristics are very different. A minor population detected in the dispersion experiments could be associated with the formation of an off-pathway intermediate that protects from fiber formation more efficiently in the germ-line protein. Moreover, we found that the hydrogen bond patterns for both proteins are similar, but the lifetime for the mutant is significantly reduced; as a consequence, there is a decrease in the stability of the tertiary structure that extends throughout the protein and leads to an increase in the propensity to form amyloid fibers.
Highlights
Light-chain amyloidosis (AL) is a deadly disease, caused by the deposition of immunoglobulin light chain (LC) amyloid fibrils in organs, resulting in organ failure and eventually death [1]
The theoretical translational diffusion coefficient predicted by hydrodynamic calculations from the coordinates of 6aJL2 (PDB entry 2MMX) and 6aJL2-R24G (PDB entry 2MKW) with hydroPRO [19] software were 1.263 × 10−7 cm2/s and 1.261 × 10−7 cm2/s, respectively
Dynamic Light Scattering (DLS) measurements of the proteins showed an apparent radius of ~2.1 nm and ~2.2 nm corresponding to a diffusion coefficient of ~1.17 × 10−7 cm2/s and ~1.11 × 10−7 for 6aJL2 and 6aJL2-R24G respectively; this shows a good agreement with the theoretical values (Figure S1)
Summary
Light-chain amyloidosis (AL) is a deadly disease, caused by the deposition of immunoglobulin light chain (LC) amyloid fibrils in organs, resulting in organ failure and eventually death [1]. It is the most common systemic amyloidosis (~70%) and is triggered by a proliferative monoclonal population of plasma cells that overexpress LC proteins [1,2]. Once these immunoglobin LC proteins are in the bloodstream, they misfold and aggregate as amyloid fibrils in tissues and organs, affecting, most frequently, kidneys (52%), heart (25%), liver (8%), and peripheral nervous system (8%).
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