Structural characterization of the partially folded intermediates of an immunoglobulin light chain leading to amyloid fibrillation and amorphous aggregation.
Immunoglobulin light chain deposition diseases involve various types of extracellular deposition of light chain variable domains, including amyloid fibrils and amorphous deposits. The decreased thermodynamic stability of the light chain is believed to be the major factor leading to fibrillation. However, the differences in the nature of the deposits among the light chain deposition diseases raise the question of whether the mechanisms leading to fibrillar or amorphous aggregation is different. In this study, we generated two partially folded intermediates of the light chain variable domain SMA in the presence of guanidine hydrochloride (GuHCl) and characterized their conformations. The more unfolded intermediate formed fibrils most rapidly, while the more native-like intermediate predominantly led to amorphous deposits. The results also show that the monomeric, rather than the dimeric state, was critical for fibrillation. The data also indicate that fibril elongation involves addition of a partially unfolded intermediate, rather than the native state. We postulate that a more highly unfolded intermediate is more suited to undergo the topological rearrangements necessary to form amyloid fibrils than a more structured one and that this also correlates with increased destabilization. In the case of light chain aggregation, it appears that more native-like intermediate conformations are more prone to form amorphous deposits.
Qin
Zhijie
Z
Department of Chemistry & Biochemistry, University of California, Santa Cruz, California 95064, USA.
Hu
Dongmei
D
Zhu
Min
M
Fink
Anthony L
AL
D000682:Amyloid / Q000096:biosynthesis* / Q000648:ultrastructure; D002942:Circular Dichroism; D005454:Fluorescence Polarization; D019791:Guanidine / Q000494:pharmacology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000187:drug effects; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D008961:Models, Structural; D017510:Protein Folding; D013050:Spectrometry, Fluorescence
D000682:Amyloid; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D019791:Guanidine