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

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

Journal Article · Wed Nov 18 00:00:00 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.

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

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

Grant/Contract Number:: AG048120; R25GM055052

OSTI ID:: 1238288

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

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 37 works

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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
Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis Nuvolone, Mario; Merlini, Giampaolo Expert Opinion on Therapeutic Targets, Vol. 21, Issue 12 https://doi.org/10.1080/14728222.2017.1398235	journal	October 2017
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