Inhibition of Light Chain 6aJL2-R24G Amyloid Fiber Formation Associated with Light Chain Amyloidosis

Pelaez-Aguilar, A.E.; Rivillas‐Acevedo, Lina; French-Pacheco, Leidys; Valdés-García, Gilberto; Maya-Martinez, Roberto; Pastor, Nina; Amero, Carlos

doi:10.1021/acs.biochem.5b00288

Cited by 16 publications

(21 citation statements)

References 55 publications

(99 reference statements)

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“…S-11). In conclusion, these and previously published results point to EGCG as a generic binder [34][35][36][37][38][39][40][41][42] and modulator 41,42 of protein structure.…”

Section: Egcg Binding Promotes As Compactionsupporting

confidence: 79%

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

et al. 2016

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The intrinsically disordered and amyloidogenic protein -synuclein (AS) has been linked to several neurodegenerative states, including Parkinson's disease. Here, nano-electrospray-ionization mass spectrometry (nano-ESI-MS), ion mobility (IM), and native top-down electron transfer dissociation (ETD) techniques are employed to study AS interaction with small molecules known to modulate its aggregation, such as epigallocatechin-3-gallate (EGCG) and dopamine (DA). The complexes formed by the two ligands under identical conditions reveal peculiar differences. While EGCG engages AS in compact conformations, DA preferentially binds to the protein in partially extended conformations. The two ligands also have different effects on AS structure as assessed by IM, with EGCG leading to protein compaction and DA to its extension. Native top-down ETD on the protein-ligand complexes shows how the different observed modes of binding of the two ligands could be related to their known opposite effects on AS aggregation. The results also show that the protein can bind either ligand in the absence of any covalent modifications, such as e.g. oxidation.

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“…S-11). In conclusion, these and previously published results point to EGCG as a generic binder [34][35][36][37][38][39][40][41][42] and modulator 41,42 of protein structure.…”

Section: Egcg Binding Promotes As Compactionsupporting

confidence: 79%

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

et al. 2016

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“…Analysis of electron micrographs and ThT assays indicates that increasing the concentration of methylene blue or sulfasalazine hinders the formation of amyloid fibrils. One of the molecules from our screen, epigallocatechin gallate, was recently suggested to hinder the formation of amyloid fibrils, yet in our experiments it did not show any effect ( Pelaez-Aguilar et al, 2015 ).…”

Section: Discussionmentioning

confidence: 70%

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

Brumshtein

Esswein

Salwiński

et al. 2015

eLife

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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.DOI: http://dx.doi.org/10.7554/eLife.10935.001

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“…The model protein 6aJL2, a recombinant (r) V L protein within the λ6 subgroup, has a particularly amyloidogenic mutant 6aJL2‐R24G (one should note that here we use continuous numbering of the amino‐acid residues along the protein; an alternative numbering scheme in which Gly24 becomes Gly25 exists). Both proteins have been comprehensively characterized by in vitro fibrillization, and their monomer structures have been determined by X‐ray crystallography and solution‐state NMR .…”

Section: Figurementioning

confidence: 99%

A Substantial Structural Conversion of the Native Monomer Leads to in‐Register Parallel Amyloid Fibril Formation in Light‐Chain Amyloidosis

et al. 2019

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Amyloid light‐chain (AL) amyloidosis is a rare disease in which plasma‐cell‐produced monoclonal immunoglobulin light chains misfold and become deposited as fibrils in the extracellular matrix. λ6 subgroup light chains are particularly fibrillogenic, and around 25 % of amyloid‐associated λ6 light chains exist as the allotypic G24R variant that renders the protein less stable. The molecular details of this process, as well as the structures of the fibrils, are unknown. We have used solid‐state NMR to investigate different fibril polymorphs. The secondary structures derived from NMR predominantly show β‐strands, including in former turn or helical regions, and provide a molecular basis for previously identified fibrillogenic hotspots. We have determined, by using differentially 15N:13C‐labeled samples, that the β‐strands are stacked in‐register parallel in the fibrils. This supramolecular arrangement shows that the native globular folds rearrange substantially upon fibrillization, and rules out the previously hypothesized fibril formation from native monomers.

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Inhibition of Light Chain 6aJL2-R24G Amyloid Fiber Formation Associated with Light Chain Amyloidosis

Cited by 16 publications

References 55 publications

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

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

A Substantial Structural Conversion of the Native Monomer Leads to in‐Register Parallel Amyloid Fibril Formation in Light‐Chain Amyloidosis

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