Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 VL domain and stabilise an unexpected partially open LC dimer in which the two VL domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.

Nanobodies Counteract the Toxicity an Amyloidogenic Light Chain by Stabilizing a Partially Open Dimeric Conformation / Broggini, L.; Barzago, M. M.; Speranzini, V.; Schulte, T.; Sonzini, F.; Giono, M.; Romeo, M.; Milani, P.; Caminito, S.; Mazzini, G.; Rognoni, P.; Merlini, G.; Pappone, C.; Anastasia, L.; Nuvolone, M.; Palladini, G.; Diomede, L.; Ricagno, S.. - In: JOURNAL OF MOLECULAR BIOLOGY. - ISSN 0022-2836. - 435:24(2023). [10.1016/j.jmb.2023.168320]

Nanobodies Counteract the Toxicity an Amyloidogenic Light Chain by Stabilizing a Partially Open Dimeric Conformation

Romeo M.;Merlini G.;Pappone C.;Anastasia L.;
2023-01-01

Abstract

Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 VL domain and stabilise an unexpected partially open LC dimer in which the two VL domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.
2023
AL amyloidosis
crystal structure
fold stabilization
soluble cardiotoxicity
specific ligands
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/166868
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