Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain

Brumshtein, Boris; Esswein, Shannon R.; Salwinski, Lukasz; Phillips, Martin L.; Ly, Alan T.; Cascio, Duilio; Sawaya, Michael R.; Eisenberg, David S.

doi:10.7554/eLife.10935

Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain

Journal Article · Tue Nov 17 23:00:00 EST 2015 · eLife

DOI:https://doi.org/10.7554/eLife.10935· OSTI ID:1238288

Brumshtein, Boris ^[1]; ^[1]; Salwinski, Lukasz ^[1]; Phillips, Martin L. ^[2]; Ly, Alan T. ^[1]; Cascio, Duilio ^[1]; Sawaya, Michael R. ^[1]; Eisenberg, David S. ^[1]

UCLA, Los Angeles, CA (United States); UCLA-DOE Inst. for Genomics and Proteomics, Los Angeles, CA (United States)
UCLA-DOE Inst. for Genomics and Proteomics, Los Angeles, CA (United States); UCLA, Los Angeles, CA (United States)

Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; National Inst. of General Medical Sciences

OSTI ID:: 1238288

Journal Information:: eLife, Journal Name: eLife Journal Issue: 11, 2015 Vol. 4; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Stabilization of amyloidogenic immunoglobulin light chains by small molecules Morgan, Gareth J.; Yan, Nicholas L.; Mortenson, David E. Proceedings of the National Academy of Sciences, Vol. 116, Issue 17 https://doi.org/10.1073/pnas.1817567116	journal	April 2019
Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate Andrich, Kathrin; Hegenbart, Ute; Kimmich, Christoph Journal of Biological Chemistry, Vol. 292, Issue 6 https://doi.org/10.1074/jbc.m116.750323	journal	December 2016
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