ArticleJournal of molecular biology2016
The Kinetic Stability of a Full-Length Antibody Light Chain Dimer Determines whether Endoproteolysis Can Release Amyloidogenic Variable Domains.
Article in Journal of molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 93 citations in OpenAlex.
- Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry.Journal of molecular biology · 2026Article
- When AL amyloidosis meets the liver: integrating clinical insight and current understanding.Annals of hematology · 2026Review
- Cryo-EM structures of light chain fibrils from abdominal fat biopsies of multiple myeloma patients.Nature communications · 2026Article
- Small molecule stabilization of diverse amyloidogenic immunoglobulin light chains revealed by hydrogen-deuterium exchange mass spectrometry.bioRxiv : the preprint server for biology · 2026Article
- Cryo-EM structure of renal AL amyloid fibrils from a patient with λ1 light chain amyloidosis.Nature communications · 2025Article
- In vitro and in vivo disease models of cardiac amyloidosis: progress, pitfalls, and potential.Cardiovascular research · 2025Review
- Tracking reduction-induced molecular changes in pathological free light chains by SV-AUC.European biophysics journal : EBJ · 2025Article
- Recent developments in systemic light-chain amyloidosis prognosis and treatment.Future cardiology · 2025Review
- Light Chain (AL) Amyloidosis Masquerading as Scleroderma: A Diagnostic Challenge.Journal of hematology · 2025Article
- A mouse model of cardiac immunoglobulin light chain amyloidosis reveals insights into tissue accumulation and toxicity of amyloid fibrils.Nature communications · 2025Article
- Clone-specific residue changes at multiple positions are associated with amyloid formation by antibody light chains.Frontiers in immunology · 2025Article
- Discovery of Potent and Selective Pyridone-Based Small Molecule Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains.Journal of medicinal chemistry · 2024Article
- Conformational Differences in the Light Chain Constant Domain of Immunoglobulin G and Free Light Chain May Influence Proteolysis in AL Amyloidosis.Journal of molecular biology · 2024Article
- Predicting Structural Consequences of Antibody Light Chain N-Glycosylation in AL Amyloidosis.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Cardiac Amyloidosis: State-of-the-Art Review in Molecular Pathology.Current issues in molecular biology · 2024Review
- Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis.Nature communications · 2024Article
- Biophysical characterization of human-cell-expressed, full-length κI O18/O8, AL-09, λ6a, and Wil immunoglobulin light chains.Biochimica et biophysica acta. Proteins and proteomics · 2024Article
- Kinetic evidence for multiple aggregation pathways in antibody light chain variable domains.Protein science : a publication of the Protein Society · 2024Article
- Crystal Structures of Diaryl Hydrazone and Sulfone Stabilizers in Complex with an Amyloidogenic Light Chain Reveal an Alternate Ligand-Binding Cavity.Israel journal of chemistry · 2023Article
- Pharmacological stabilization of the native state of full-length immunoglobulin light chains to treat light chain amyloidosis.Current opinion in chemical biology · 2023Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Light chain (LC) amyloidosis (AL amyloidosis) appears to be caused by the misfolding, or misfolding and aggregation of an antibody LC or fragment thereof and is fatal if untreated. LCs are secreted from clonally expanded plasma cells, generally as disulfide-linked dimers, with each monomer comprising one constant and one variable domain. The energetic contribution of each domain and the role of endoproteolysis in AL amyloidosis remain unclear. To investigate why only some LCs form amyloid and cause organ toxicity, we measured the aggregation propensity and kinetic stability of LC dimers and their associated variable domains from AL amyloidosis patients and non-patients. All the variable domains studied readily form amyloid fibrils, whereas none of the full-length LC dimers, even those from AL amyloidosis patients, are amyloidogenic. Kinetic stability-that is, the free energy difference between the native state and the unfolding transition state-dictates the LC's unfolding rate. Full-length LC dimers derived from AL amyloidosis patients unfold more rapidly than other full-length LC dimers and can be readily cleaved into their component domains by proteases, whereas non-amyloidogenic LC dimers are more kinetically stable and resistant to endoproteolysis. Our data suggest that amyloidogenic LC dimers are kinetically unstable (unfold faster) and are thus susceptible to endoproteolysis that results in the release amyloidogenic LC fragments, whereas other LCs are not as amenable to unfolding and endoproteolysis and are therefore aggregation resistant. Pharmacologic kinetic stabilization of the full-length LC dimer could be a useful strategy to treat AL amyloidosis.
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