Localized conformational changes trigger the pH-induced fibrillogenesis of an amyloidogenic λ light chain protein

Publication date: July 2018
Source:Biochimica et Biophysica Acta (BBA) – General Subjects, Volume 1862, Issue 7
Author(s): Isabel Velázquez-López, Gilberto Valdés-García, Sergio Romero Romero, Roberto Maya Martínez, Ana I. Leal-Cervantes, Miguel Costas, Rosana Sánchez-López, Carlos Amero, Nina Pastor, D. Alejandro Fernández Velasco
Solvent conditions modulate the expression of the amyloidogenic potential of proteins. In this work the effect of pH on the fibrillogenic behavior and the conformational properties of 6aJL2, a model protein of the highly amyloidogenic variable light chain λ6a gene segment, was examined. Ordered aggregates showing the ultrastructural and spectroscopic properties observed in amyloid fibrils were formed in the 2.0–8.0 pH range. At pH <3.0 a drastic decrease in lag time and an increase in fibril formation rate were found. In the 4.0–8.0 pH range there was no spectroscopic evidence for significant conformational changes in the native state. Likewise, heat capacity measurements showed no evidence for residual structure in the unfolded state. However, at pH <3.0 stability is severely decreased and the protein suffers conformational changes as detected by circular dichroism, tryptophan and ANS fluorescence, as well as by NMR spectroscopy. Molecular dynamics simulations indicate that acid-induced conformational changes involve the exposure of the loop connecting strands E and F. These results are compatible with pH-induced changes in the NMR spectra. Overall, the results indicate that the mechanism involved in the acid-induced increase in the fibrillogenic potential of 6aJL2 is profoundly different to that observed in κ light chains, and is promoted by localized conformational changes in a region of the protein that was previously not known to be involved in acid-induced light chain fibril formation. The identification of this region opens the potential for the design of specific inhibitors.

Graphical abstract

image