ArticleJournal of molecular biology2014
Kinetic control in protein folding for light chain amyloidosis and the differential effects of somatic mutations.
Article in Journal of molecular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 58 citations in OpenAlex.
- Amyloid Light Chain Proteins in Cardiovascular Disease: Pathogenesis and Emerging Therapies for Cardiac Amyloidosis.Pharmaceutical research · 2025Review
- In vitro and in vivo disease models of cardiac amyloidosis: progress, pitfalls, and potential.Cardiovascular research · 2025Review
- 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
- 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
- Pharmacological stabilization of the native state of full-length immunoglobulin light chains to treat light chain amyloidosis.Current opinion in chemical biology · 2023Review
- Molecular Research on Amyloidosis.International journal of molecular sciences · 2023Article
- Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.Frontiers in immunology · 2023Review
- Review
- Molecular Mechanism of Pathogenesis and Treatment Strategies for AL Amyloidosis.International journal of molecular sciences · 2022Review
- Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM.Nature communications · 2021Article
- AL Amyloidosis: Current Chemotherapy and Immune Therapy Treatment Strategies:JACC. CardioOncology · 2021Review
- Early events in light chain aggregation at physiological pH reveal new insights on assembly, stability, and aggregate dissociation.Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2021Article
- Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease.Kidney international reports · 2020Review
- Mechanistic Insights into the Early Events in the Aggregation of Immunoglobulin Light Chains.Biochemistry · 2019Article
- Assays for Light Chain Amyloidosis Formation and Cytotoxicity.Methods in molecular biology (Clifton, N.J.) · 2019Article
- Immunoglobulin light chain amyloid aggregation.Chemical communications (Cambridge, England) · 2018Review
- Incomplete Refolding of Antibody Light Chains to Non-Native, Protease-Sensitive Conformations Leads to Aggregation: A Mechanism of Amyloidogenesis in Patients?Biochemistry · 2017Article
- Concurrent structural and biophysical traits link with immunoglobulin light chains amyloid propensity.Scientific reports · 2017Article
- Kinetic stability and sequence/structure studies of urine-derived Bence-Jones proteins from multiple myeloma and light chain amyloidosis patients.Biophysical chemistry · 2017Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Light chain amyloidosis is a devastating disease where immunoglobulin light chains form amyloid fibrils, resulting in organ dysfunction and death. Previous studies have shown a direct correlation between the protein thermodynamic stability and the propensity for amyloid formation for some proteins involved in light chain amyloidosis. Here we investigate the effect of somatic mutations on protein stability and in vitro fibril formation of single and double restorative mutants of the protein AL-103 compared to the wild-type germline control protein. A scan rate dependence and hysteresis in the thermal unfolding and refolding was observed for all proteins. This indicates that the unfolding/refolding reaction is kinetically determined with different kinetic constants for unfolding and refolding even though the process remains experimentally reversible. Our structural analysis of AL-103 and AL-103 delP95aIns suggests a kinetic coupling of the unfolding/refolding process with cis-trans prolyl isomerization. Our data reveal that the deletion of proline 95a (AL-103 delP95aIns), which removes the trans-cis di-proline motif present in the patient protein AL-103, results in a dramatic increment in the thermodynamic stability and a significant delay in fibril formation kinetics with respect to AL-103. Fibril formation is pH dependent; all proteins form fibrils at pH2; reactions become slower and more stochastic as the pH increases up to pH7. Based on these results, we propose that, in addition to thermodynamic stability, kinetic stability (possibly influenced by the presence of cis proline 95a) plays a major role in the AL-103 amyloid fibril formation process.
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