Structural Transformations of Oligomeric Intermediates in The Fibrillation of The Immunoglobulin Light Chain LEN
Document Type
Article
Publication Date
2003
Keywords
Amides, Nanofibers, Oligomers, Peptides and Proteins, Stability
Digital Object Identifier (DOI)
https://doi.org/10.1021/bi034652m
Abstract
LEN is a κIV immunoglobulin light chain variable domain from a patient suffering from multiple myeloma but with no evidence of amyloid fibrils. However, fibrils are formed when LEN solutions are agitated under mildly destabilizing conditions. Surprisingly, an inverse concentration dependence was observed on the kinetics of fibril formation because of the formation of off-pathway soluble oligomers at high protein concentration. Despite the fact that most of the protein is present in the off-pathway intermediates at relatively early times of aggregation, eventually all the protein forms fibrils. Thus, a structural rearrangement from the non fibril-prone off-pathway oligomers to a more fibril-prone species must occur. A variety of techniques were used to monitor changes in the size, secondary structure, solvent accessibility, and intrinsic stability of the oligomers, as a function of incubation time. The structural rearrangement was accompanied by a significant increase of disordered secondary structure, an increase in solvent accessibility, and a decrease in intrinsic stability of the soluble oligomeric species. We conclude that fibrils arise from the oligomers containing a less stable conformation of LEN, either directly or via dissociation. This is the first fibrillating system in which soluble off-pathway oligomeric intermediates have been shown to be the major transient species and in which fibrillation occurs from a relatively unfolded conformation present in these intermediates.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Biochemistry, v. 42, issue 26, p. 8094-8104
Scholar Commons Citation
Souillac, Pierre O.; Uversky, Vladimir N.; and Fink, Anthony L., "Structural Transformations of Oligomeric Intermediates in The Fibrillation of The Immunoglobulin Light Chain LEN" (2003). Molecular Medicine Faculty Publications. 711.
https://digitalcommons.usf.edu/mme_facpub/711
