Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains.

ABSTRACT: Light chain amyloidosis (AL) is caused by the aberrant overproduction of immunoglobulin light chains (LCs). The resulting abnormally high LC concentrations in blood lead to deposit formation in the heart and other target organs. Organ damage is caused not only by the accumulation of bulky amyloid deposits, but extensive clinical data indicate that circulating soluble LCs also exert cardiotoxic effects. The nematode C. elegans has been validated to recapitulate LC soluble toxicity in vivo, and in such a model a role for copper ions in increasing LC soluble toxicity has been reported. Here, we applied microscale thermophoresis, isothermal calorimetry and thermal melting to demonstrate the specific binding of Cu²⁺ to the variable domain of amyloidogenic H7 with a sub-micromolar affinity. Histidine residues present in the LC sequence are not involved in the binding, and yet their mutation to Ala reduces the soluble toxicity of H7. Copper ions bind to and destabilize the variable domains and induce a limited stabilization in this domain. In summary, the data reported here, elucidate the biochemical bases of the Cu²⁺-induced toxicity; moreover, they also show that copper binding is just one of the several biochemical traits contributing to LC soluble in vivo toxicity.

SUBMITTER: Russo R

PROVIDER: S-EPMC8780072 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

AMYLOIDOGENIC LIGHT CHAINS IMPAIR PLASMA CELL SURVIVAL

Project description:We used lentiviral vectors to generate cell lines expressing LCs from patients suffering from AL amyloidosis.

2023-06-01 | GSE176119 | GEO

Investigating heart-specific toxicity of amyloidogenic immunoglobulin light chains: A lesson from C. elegans.

Project description:Abnormalities in protein folding are involved in many localized and systemic diseases, all of which are characterized by insoluble amyloid formation and deposition. In immunoglobulin light chain (LC) amyloidosis, the most frequent systemic form of amyloidosis, the amyloid involvement of the heart dictates the prognosis and the elucidation of the mechanism of heart targeting and toxicity is essential for designing and testing new effective treatments. To this end, the availability of an appropriate animal model is crucial. We recently described the use of C. elegans as an innovative experimental system to investigate in vivo the pathogenic effects of monoclonal LC. This idea stems from the knowledge that the worm's pharynx is an "ancestral heart" with the additional ability to recognize stressor compounds. The feeding of worms with LC purified from patients suffering from cardiomyopathy, selectively and permanently impaired the pharyngeal function. This irreversible damage resulted in time, in a significant reduction in the lifespan of worms. We also reported that the ability of LC to generate reactive oxygen species was associated with their toxic effects and was counteracted by anti-oxidant compounds. This new nematode-based assay represents a promising model for elucidating the heart-specific toxicity of LC and for a rapid screening of new therapeutic strategies.

| S-EPMC4588172 | biostudies-other

Structural alterations within native amyloidogenic immunoglobulin light chains.

Project description:Amyloid diseases are characterized by the misfolding of a precursor protein that leads to amyloid fibril formation. Despite the fact that there are different precursors, some commonalities in the misfolding mechanism are thought to exist. In light chain amyloidosis (AL), the immunoglobulin light chain forms amyloid fibrils that deposit in the extracellular space of vital organs. AL proteins are thermodynamically destabilized compared to non-amyloidogenic proteins and some studies have linked this instability to increased fibril formation rates. Here we present the crystal structures of two highly homologous AL proteins, AL-12 and AL-103. This structural study shows that these proteins retain the canonical germ line dimer interface. We highlight important structural alterations in two loops flanking the dimer interface and correlate these results with the somatic mutations present in AL-12 and AL-103. We suggest that these alterations are informative structural features that are likely contributing to protein instability that leads to conformational changes involved in the initial events of amyloid formation.

| S-EPMC2840394 | biostudies-literature

A functional assay to identify amyloidogenic light chains.

Project description:IntroductionMultiple myeloma (MM) and light chain monoclonal gammopathy of undetermined significance (LCMGUS) are plasma cell disorders associated with the secretion of monoclonal free light-chain (LC) proteins. Due to the high concentrations of LC in circulation, both of these populations are at risk for developing LC-associated amyloidosis (AL) - a protein misfolding disease characterized by the deposition of LC protein fibrils in organs and tissues, leading to dysfunction and significant morbidity. At present, accurate identification of subjects at risk for developing amyloidosis is not possible, but with the advent of novel, amyloid-targeted therapies, identification of pre-symptomatic individuals is of clinical import.MethodsTo address this, a competition assay has been developed to discern LC proteins with enhanced amyloidogenic potential. Numerous factors that may influence the efficacy of the assay have been evaluated to yield optimal conditions.ResultsUsing a panel of nine patient-derived LC, we have demonstrated that amyloid-associated LC inhibited the recruitment of a biotinyl-λ6 variable domain by homologous amyloid-like fibrils significantly more than MM LC (p < .01).ConclusionThe assay accurately discriminated AL from MM patient populations, suggesting that it may aid in the identification of patients with monoclonal gammopathies who have an increased risk of developing amyloidosis.

| S-EPMC6333307 | biostudies-literature

AMYLOIDOGENIC LIGHT CHAINS IMPAIR PLASMA CELL SURVIVAL

Project description:AMYLOIDOGENIC LIGHT CHAINS IMPAIR PLASMA CELL SURVIVAL

| PRJNA734939 | ENA

Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture.

Project description:Light-chain amyloidosis (AL) is a devastating protein-misfolding disease characterized by abnormal proliferation of plasma cells in the bone marrow that secrete monoclonal immunoglobulin light chains that misfold and form amyloid fibrils, thus causing organ failure and death. Numerous reports on different protein-misfolding diseases show that soluble oligomeric species populated by amyloidogenic proteins can be quite toxic to cells. However, it is not well established whether the soluble immunoglobulin light-chain species found in circulation in patients with AL are toxic to cells in target organs. We determined the cellular toxicity of two well-characterized light-chain variable domain proteins from cardiac AL patients and their corresponding germline protein, devoid of somatic mutations. Our results show that the soluble form of the AL proteins we characterized are toxic to cardiomyocytes, and that the species found in cell culture correspond, for the most part, to the species present in circulation in these patients.

| S-EPMC3032327 | biostudies-literature

Stabilization of amyloidogenic immunoglobulin light chains by small molecules.

Project description:In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC-LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.

| S-EPMC6486714 | biostudies-literature

Toxicity of LCDD monoclonal Ig free light chains

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-05-14 | GSE119050 | GEO

Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains.

Project description:Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). The huge variety of antibody sequences puts a serious challenge to drug discovery. The green tea polyphenol epigallocatechin-3-gallate (EGCG) is known to interfere with fibril formation in general. Here we present solution- and solid-state NMR studies as well as MD simulations to characterise the interaction of EGCG with LC variable domains. We identified two distinct EGCG binding sites, both of which include a proline as an important recognition element. The binding sites were confirmed by site-directed mutagenesis and solid-state NMR analysis. The EGCG-induced protein complexes are unstructured. We propose a general mechanistic model for EGCG binding to a conserved site in LCs. We find that EGCG reacts selectively with amyloidogenic mutants. This makes this compound a promising lead structure, that can handle the immense sequence variability of antibody LCs.

| S-EPMC5269747 | biostudies-literature

Molecular mechanism of amyloidogenic mutations in hypervariable regions of antibody light chains.

Project description:Systemic light chain (AL) amyloidosis is a fatal protein misfolding disease in which excessive secretion, misfolding, and subsequent aggregation of free antibody light chains eventually lead to deposition of amyloid plaques in various organs. Patient-specific mutations in the antibody VL domain are closely linked to the disease, but the molecular mechanisms by which certain mutations induce misfolding and amyloid aggregation of antibody domains are still poorly understood. Here, we compare a patient VL domain with its nonamyloidogenic germline counterpart and show that, out of the five mutations present, two of them strongly destabilize the protein and induce amyloid fibril formation. Surprisingly, the decisive, disease-causing mutations are located in the highly variable complementarity determining regions (CDRs) but exhibit a strong impact on the dynamics of conserved core regions of the patient VL domain. This effect seems to be based on a deviation from the canonical CDR structures of CDR2 and CDR3 induced by the substitutions. The amyloid-driving mutations are not necessarily involved in propagating fibril formation by providing specific side chain interactions within the fibril structure. Rather, they destabilize the VL domain in a specific way, increasing the dynamics of framework regions, which can then change their conformation to form the fibril core. These findings reveal unexpected influences of CDR-framework interactions on antibody architecture, stability, and amyloid propensity.

| S-EPMC7949129 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data