The Role of Protein Thermodynamics and Primary Structure in Fibrillogenesis of Variable Domains from Immunoglobulin Light Chains

Journal of the American Chemical Society
Enrico RennellaLewis E Kay

Abstract

Immunoglobulin light-chain amyloidosis is a protein aggregation disease that leads to proteinaceous deposits in a variety of organs in the body and, if untreated, ultimately results in death. The mechanisms by which light-chain aggregation occurs are not well understood. Here we have used solution NMR spectroscopy and biophysical studies to probe immunoglobulin variable domain λV6-57 VL aggregation, a process that appears to drive the degenerative phenotypes in amyloidosis patients. Our results establish that aggregation proceeds via the unfolded state. We identify, through NMR relaxation experiments recorded on the unfolded domain ensemble, a series of hotspots that could be involved in the initial phases of aggregate formation. Mutational analysis of these hotspots reveals that the region that includes K16-R24 is particularly aggregation prone. Notably, this region includes the site of the R24G substitution, a mutation that is found in variable domains of λ light-chain deposits in 25% of patients. The R24G λV6-57 VL domain aggregates more rapidly than would be expected on the basis of thermodynamic stability alone, while substitutions in many of the aggregation-prone regions significantly slow down fibril formation.

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Citations

Apr 15, 2020·Nature Communications·Jessica S EboDavid J Brockwell
Jul 30, 2020·Expert Review of Hematology·Marco BassetGiampaolo Merlini
Jan 29, 2021·The Journal of Biological Chemistry·Georg J RottenaicherJohannes Buchner
Mar 19, 2021·Proceedings of the National Academy of Sciences of the United States of America·Máximo Sanz-HernándezAlfonso De Simone
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gareth J Morgan

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