Indexed on: 12 Jan '17Published on: 12 Jan '17Published in: Biochemistry
Light chain (AL) amyloidosis is a lethal disease characterized by the deposition of the immunoglobulin light chain into amyloid fibrils, resulting in organ dysfunction and failure. Amyloid fibrils have the ability to self-propagate recruiting soluble protein into the fibril by a nucleation-polymerization mechanism, characteristic of auto-catalytic reactions. Experimental data suggest the existence of a critical concentration to initiate fibril formation. As such, the initial concentration of soluble amyloidogenic protein is expected to have a profound effect on the rate of fibril formation. In this work, we present in vitro evidence that fibril formation rates for AL light chains are affected by the protein concentration in a differential manner. De novo reactions of the proteins with the fastest amyloid kinetics (AL-09, AL-T05 and AL-103) do not present protein concentration dependence. Seeded reactions however, presented small protein concentration dependence. For AL-12, seeded and protein concentration dependence data suggests a synergistic effect for recruitment and elongation at low protein concentrations, while reactions of κI had a poor efficiency to nucleate and elongate preformed fibrils. Additionally, co-aggregation and cross seeding of κI variable domain (VL) and the κI full length (FL) light chain indicate that the presence of the constant domain in κI FL modulates fibril formation, facilitating the recruitment of κI VL. Together, these results indicate that the dominant process in the fibril formation varies among the AL proteins tested with a differential dependence of the protein concentration.
Indexed on: 17 Nov '10
Published on: 17 Nov '10 in Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis