ArticleProtein science : a publication of the Protein Society2015
Mutations can cause light chains to be too stable or too unstable to form amyloid fibrils.
Article in Protein science : a publication of the Protein Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- Generation of Infectious Prions Amenable to Site-Specific Click Chemistry.ACS chemical biology · 2026Article
- Cryo-EM structures of light chain fibrils from abdominal fat biopsies of multiple myeloma patients.Nature communications · 2026Article
- Clone-specific residue changes at multiple positions are associated with amyloid formation by antibody light chains.Frontiers in immunology · 2025Article
- Amyloidogenesis of SARS-CoV-2 delta plus and omicron variants receptor-binding domain (RBD): impact of SUMO fusion tag.Biotechnology letters · 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
- Role of complementarity-determining regions 1 and 3 in pathologic amyloid formation by human immunoglobulin κ1 light chains.Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2023Article
- A porphyrin-based molecular cage guided by designed local-electric field is highly selective and efficient.Chemical science · 2023Article
- Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.Frontiers in immunology · 2023Review
- Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains.International journal of molecular sciences · 2022Article
- Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis.Biophysical chemistry · 2022Review
- A Conservative Point Mutation in a Dynamic Antigen-binding Loop of Human Immunoglobulin λ6 Light Chain Promotes Pathologic Amyloid Formation.Journal of molecular biology · 2021Article
- 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
- Seeded fibrils of the germline variant of human λ-III immunoglobulin light chain FOR005 have a similar core as patient fibrils with reduced stability.The Journal of biological chemistry · 2020Article
- 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
- Immunoglobulin light chain amyloid aggregation.Chemical communications (Cambridge, England) · 2018Review
- Concurrent structural and biophysical traits link with immunoglobulin light chains amyloid propensity.Scientific reports · 2017Article
- sw ApoMb Amyloid Aggregation under Nondenaturing Conditions: The Role of Native Structure Stability.Biophysical journal · 2017Article
- Effect of amino acid mutations on the conformational dynamics of amyloidogenic immunoglobulin light-chains: A combined NMR and in silico study.Scientific reports · 2017Article
- Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate.The Journal of biological chemistry · 2017Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Light chain (AL) amyloidosis is an incurable human disease, where the amyloid precursor is a misfolding-prone immunoglobulin light-chain. Here, we identify the role of somatic mutations in the structure, stability and in vitro fibril formation for an amyloidogenic AL-12 protein by restoring four nonconservative mutations to their germline (wild-type) sequence. The single restorative mutations do not affect significantly the native structure, the unfolding pathway, and the reversibility of the protein. However, certain mutations either decrease (H32Y and H70D) or increase (R65S and Q96Y) the protein thermal stability. Interestingly, the most and the least stable mutants, Q96Y and H32Y, do not form amyloid fibrils under physiological conditions. Thus, Q96 and H32 are key residues for AL-12 stability and fibril formation and restoring them to the wild-type residues preclude amyloid formation. The mutants whose equilibrium is shifted to either the native or unfolded states barely sample transient partially folded states, and therefore do not form fibrils. These results agree with previous observations by our laboratory and others that amyloid formation occurs because of the sampling of partially folded states found within the unfolding transition (Blancas-Mejia and Ramirez-Alvarado, Ann Rev Biochem 2013;82:745-774). Here we provide a new insight on the AL amyloidosis mechanism by demonstrating that AL-12 does not follow the established thermodynamic hypothesis of amyloid formation. In this hypothesis, thermodynamically unstable proteins are more prone to amyloid formation. Here we show that within a thermal stability range, the most stable protein in this study is the most amyloidogenic protein.
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