Document Type
Article
Publication Date
2002
Digital Object Identifier (DOI)
https://doi.org/10.1074/jbc.M109229200
Abstract
Light chain amyloidosis involves the systemic pathologic deposition of monoclonal light chain variable domains of immunoglobulins as insoluble fibrils. The variable domain LEN was obtained from a patient who had no overt amyloidosis; however, LEN forms fibrils in vitro, under mildly destabilizing conditions. The in vitro kinetics of fibrillation were investigated using a wide variety of probes. The rate of fibril formation was highly dependent on the initial protein concentration. In contrast to most amyloid systems, the kinetics became slower with increasing LEN concentrations. At high protein concentrations a significant lag in time was observed between the conformational changes and the formation of fibrils, consistent with the formation of soluble off-pathway oligomeric species and a branched pathway. The presence of off-pathway species was confirmed by small angle x-ray scattering. At low protein concentrations the structural rearrangements were concurrent with fibril formation, indicating the absence of formation of the off-pathway species. The data are consistent with a model for fibrillation in which a dimeric form of LEN (at high protein concentration) inhibits fibril formation by interaction with an intermediate on the fibrillation pathway and leads to formation of the off-pathway intermediate.
Rights Information
This work is licensed under a Creative Commons Attribution 4.0 License.
Was this content written or created while at USF?
No
Citation / Publisher Attribution
Journal of Biological Chemistry, v. 277, issue 15, p. 12666-12679
Scholar Commons Citation
Souillac, Pierre O.; Uversky, Vladimir N.; Millett, Ian S.; Khurana, Ritu; Doniach, Sebastian; and Fink, Anthony L., "Elucidation of The Molecular Mechanism During The Early Events in Immunoglobulin Light Chain Amyloid Fibrillation: EVIDENCE FOR AN OFF-PATHWAY OLIGOMER AT ACIDIC Ph" (2002). Molecular Medicine Faculty Publications. 691.
https://digitalcommons.usf.edu/mme_facpub/691
