scholarly journals Heat-induced native dimerization prevents amyloid formation by variable domain from immunoglobulin light-chain REI

FEBS Journal ◽  
2017 ◽  
Vol 284 (18) ◽  
pp. 3114-3127 ◽  
Author(s):  
Marina Nawata ◽  
Hirotaka Tsutsumi ◽  
Yuta Kobayashi ◽  
Satoru Unzai ◽  
Shouhei Mine ◽  
...  
Keyword(s):  
Light Chain ◽  
Variable Domain ◽  
Amyloid Formation ◽  
Immunoglobulin Light Chain

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

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Boris Brumshtein ◽  
Shannon R Esswein ◽  
Lukasz Salwinski ◽  
Martin L Phillips ◽  
Alan T Ly ◽  
...  
Keyword(s):  
Small Molecule ◽  
Light Chain ◽  
Amyloid Fibrils ◽  
Variable Domain ◽  
Light Chains ◽  
Amyloid Formation ◽  
Immunoglobulin Light Chains ◽  
Immunoglobulin Light Chain ◽  
Small Molecule Ligands ◽  
Irreversible Aggregation

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.

Decreased Amyloidogenicity Caused by Mutational Modulation of Surface Properties of the Immunoglobulin Light Chain BRE Variable Domain

Biochemistry ◽  
2014 ◽  
Vol 53 (31) ◽  
pp. 5162-5173 ◽  
Author(s):  
Yuta Kobayashi ◽  
Hirotaka Tsutsumi ◽  
Tetsuyuki Abe ◽  
Kyohei Ikeda ◽  
Yuki Tashiro ◽  
...  
Keyword(s):  
Surface Properties ◽  
Light Chain ◽  
Variable Domain ◽  
Immunoglobulin Light Chain

Probing the role of λ6 immunoglobulin light chain dimerization in amyloid formation

2016 ◽  
Vol 1864 (4) ◽  
pp. 409-418 ◽  
Author(s):  
Mathieu Laporte Wolwertz ◽  
Phuong Trang Nguyen ◽  
Noé Quittot ◽  
Steve Bourgault
Keyword(s):  
Light Chain ◽  
Amyloid Formation ◽  
Immunoglobulin Light Chain

Immunoglobulin light chain toxicity in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Blood ◽  
2020 ◽  
Author(s):  
Sébastien Bender ◽  
Maria Victoria Ayala ◽  
Amélie Bonaud ◽  
Vincent Javaugue ◽  
Claire Carrion ◽  
...  
Keyword(s):  
Mouse Model ◽  
Light Chain ◽  
High Efficiency ◽  
Kidney Diseases ◽  
Variable Domain ◽  
Immunoglobulin Light Chain ◽  
Monoclonal Immunoglobulin ◽  
Light Chain Deposition Disease ◽  
Deposition Disease ◽  
Light Chain Deposition

Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells (PCs). High free LC levels were achieved after backcrossing with mice presenting increased PC differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on PCs demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.

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