ArticleBiochemistry2010
The critical role of the constant region in thermal stability and aggregation of amyloidogenic immunoglobulin light chain.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
- Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry.Journal of molecular biology · 2026Article
- Cryo-EM of Cardiac AL-224L Amyloid Reveals Shared Structural Motifs and Mutation-induced Differences in λ6 Light Chain Fibrils.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
- In vitro and in vivo disease models of cardiac amyloidosis: progress, pitfalls, and potential.Cardiovascular research · 2025Review
- B Cell-Derived and Non-B Cell-Derived Free Light Chains: From Generation to Biological and Pathophysiological Roles.International journal of molecular sciences · 2025Review
- An updated AL-base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis.Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2025Article
- Article
- Clone-specific residue changes at multiple positions are associated with amyloid formation by antibody light chains.Frontiers in immunology · 2025Article
- 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
- Proteomic Evidence for Amyloidogenic Cross-Seeding in Fibrinaloid Microclots.International journal of molecular sciences · 2024Article
- An updated AL-Base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis.bioRxiv : the preprint server for biology · 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
- 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 constant domain mutation in a patient-derived antibody light chain reveals principles of AL amyloidosis.Communications biology · 2023Article
- Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains.BMC biology · 2023Article
- Complete variable domain sequences of monoclonal antibody light chains identified from untargeted RNA sequencing data.Frontiers in immunology · 2023Article
- Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.Frontiers in immunology · 2023Review
- An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis.Leukemia · 2022Article
- Molecular characterization of linker and loop-mediated structural modulation and hinge motion in the C4-C5 domains of cMyBPC.Journal of structural biology · 2022Article
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Authors and funding
7 authors.
Funding
Abstract
Light chain (LC) amyloidosis (AL) is a fatal disease in which immunoglobulin LC deposit as fibrils. Although the LC amyloid-forming propensity is attributed primarily to the variable region, fibrils also contain full-length LC comprised of variable-joining (V(L)) and constant (C(L)) regions. To assess the role of C(L) in fibrillogenesis, we compared the thermal stability of full-length LC and corresponding V(L) and C(L) fragments. Protein unfolding and aggregation were monitored by circular dichroism and light scattering. A full-length λ6 LC purified from urine of a patient with AL amyloidosis showed irreversible unfolding coupled to aggregation. The transition temperature decreased at slower heating rates, indicating kinetic effects. Next, we studied five recombinant λ6 proteins: full-length amyloidogenic LC, its V(L), germline LC, germline V(L), and C(L). Amyloidogenic and germline proteins showed similar rank order of stability, V(L) < LC < C(L); hence, in the full-length LC, V(L) destabilizes C(L). Amyloidogenic proteins were less stable than their germline counterparts, suggesting that reduction in V(L) stability destabilizes the full-length LC. Thermal unfolding of the full-length amyloidogenic and germline LC required high activation energy and involved irreversible aggregation, yet the unfolding of the isolated V(L) and C(L) fragments was partially reversible. Therefore, compared to their fragments, full-length LCs are more likely to initiate aggregation during unfolding and provide a template for the V(L) deposition. The kinetic barrier for this aggregation is regulated by the stability of the V(L) region. This represents a paradigm shift in AL fibrillogenesis and suggests C(L) region as a potential therapeutic target.
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