ArticleBiochemistry2017
Incomplete Refolding of Antibody Light Chains to Non-Native, Protease-Sensitive Conformations Leads to Aggregation: A Mechanism of Amyloidogenesis in Patients?
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 31 citations in OpenAlex.
- Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry.Journal of molecular biology · 2026Article
- Small molecule stabilization of diverse amyloidogenic immunoglobulin light chains revealed by hydrogen-deuterium exchange mass spectrometry.bioRxiv : the preprint server for biology · 2026Article
- Investigating Local Sequence-Structural Attributes of Amyloidogenic Light Chain Variable Domains.Proteins · 2025Article
- 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
- Biophysical Analysis of Therapeutic Antibodies in the Early Development Pipeline.Biologics : targets & therapy · 2024Review
- 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
- Pharmacological stabilization of the native state of full-length immunoglobulin light chains to treat light chain amyloidosis.Current opinion in chemical biology · 2023Review
- Producing amyloid fibrils in vitro: A tool for studying AL amyloidosis.Biochemistry and biophysics reports · 2023Article
- A constant domain mutation in a patient-derived antibody light chain reveals principles of AL amyloidosis.Communications biology · 2023Article
- An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis.Leukemia · 2022Article
- Understanding AL amyloidosis with a little help fromFrontiers in immunology · 2022Review
- Protease-sensitive regions in amyloid light chains: what a common pattern of fragmentation across organs suggests about aggregation.The FEBS journal · 2022Article
- Article
- Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design.Journal of medicinal chemistry · 2021Article
- The Role of Protein Thermodynamics and Primary Structure in Fibrillogenesis of Variable Domains from Immunoglobulin Light Chains.Journal of the American Chemical Society · 2019Article
- Stabilization of amyloidogenic immunoglobulin light chains by small molecules.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient.Nature communications · 2019Article
- Role of domain interactions in the aggregation of full-length immunoglobulin light chains.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Storage diseases with hypertrophic cardiomyopathy phenotype.Global cardiology science & practice · 2018Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Genetic, biochemical, and pharmacologic evidence supports the hypothesis that conformationally altered or misfolded protein states enable aggregation and cytotoxicity in the systemic amyloid diseases. Reversible structural fluctuations of natively folded proteins are involved in the aggregation of many degenerative disease associated proteins. Herein, we use antibody light chains (LCs) that form amyloid fibrils in AL amyloidosis to consider an alternative hypothesis of amyloidogenesis: that transient unfolding and incomplete extracellular refolding of secreted proteins can lead to metastable, alternatively folded states that are more susceptible to aggregation or to endoproteolysis that can release aggregation-prone fragments. Refolding of full-length λ6a LC dimers comprising an interchain disulfide bond from heat- or chaotrope-denatured ensembles in buffers yields the native dimeric state as well as alternatively folded dimers and aggregates. LC variants lacking an interchain disulfide bond appear to refold fully reversibly to the native state. The conformation of a backbone peptidyl-proline amide in the LC constant domain, which is cis in the native state, may determine whether the LC refolds back to the native state. A proline to alanine (P147A) LC variant, which cannot form the native cis-amide conformation, forms amyloid fibrils from the alternatively folded ensemble, whereas all the full-length λ6a LCs we have studied to date do not form amyloid under analogous conditions. P147A LC variants are susceptible to endoproteolysis by thrombin, enabling amyloidogenesis of the fragments released. Thus, non-native LC structural ensembles containing a tyrosine 146-proline 147 trans-amide bond can initiate and propagate amyloid formation, either directly or after aberrant endoproteolysis.
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