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Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease

Light-chain amyloidosis (AL) is the most common systemic amyloidosis and is caused by the deposition of mainly insoluble immunoglobulin light chain amyloid fibrils in multiple organs, causing organ failure and eventually death. The germ-line λ6a has been implicated in AL, where a single point mutant...

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Autores principales: Maya-Martinez, Roberto, French-Pacheco, Leidys, Valdés-García, Gilberto, Pastor, Nina, Amero, Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747610/
https://www.ncbi.nlm.nih.gov/pubmed/31438515
http://dx.doi.org/10.3390/ijms20174078
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author Maya-Martinez, Roberto
French-Pacheco, Leidys
Valdés-García, Gilberto
Pastor, Nina
Amero, Carlos
author_facet Maya-Martinez, Roberto
French-Pacheco, Leidys
Valdés-García, Gilberto
Pastor, Nina
Amero, Carlos
author_sort Maya-Martinez, Roberto
collection PubMed
description Light-chain amyloidosis (AL) is the most common systemic amyloidosis and is caused by the deposition of mainly insoluble immunoglobulin light chain amyloid fibrils in multiple organs, causing organ failure and eventually death. The germ-line λ6a has been implicated in AL, where a single point mutant at amino acid 24 (6aJL2-R24G) has been observed in around 25% of patient samples. Structural analysis has shown only subtle differences between both proteins; nevertheless, 6aJL2-R24G is more prone to form amyloid fibrils. To improve our understanding of the role of protein flexibility in amyloid fibril formation, we have used a combination of solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations to complement the structural insight with dynamic knowledge. Fast timescale dynamics (ps–ns) were equivalent for both proteins, but suggested exchange events for some residues. Even though most of the intermediate dynamics (μs–ms) occurred at a similar region for both proteins, the specific characteristics are very different. A minor population detected in the dispersion experiments could be associated with the formation of an off-pathway intermediate that protects from fiber formation more efficiently in the germ-line protein. Moreover, we found that the hydrogen bond patterns for both proteins are similar, but the lifetime for the mutant is significantly reduced; as a consequence, there is a decrease in the stability of the tertiary structure that extends throughout the protein and leads to an increase in the propensity to form amyloid fibers.
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spelling pubmed-67476102019-09-27 Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease Maya-Martinez, Roberto French-Pacheco, Leidys Valdés-García, Gilberto Pastor, Nina Amero, Carlos Int J Mol Sci Article Light-chain amyloidosis (AL) is the most common systemic amyloidosis and is caused by the deposition of mainly insoluble immunoglobulin light chain amyloid fibrils in multiple organs, causing organ failure and eventually death. The germ-line λ6a has been implicated in AL, where a single point mutant at amino acid 24 (6aJL2-R24G) has been observed in around 25% of patient samples. Structural analysis has shown only subtle differences between both proteins; nevertheless, 6aJL2-R24G is more prone to form amyloid fibrils. To improve our understanding of the role of protein flexibility in amyloid fibril formation, we have used a combination of solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations to complement the structural insight with dynamic knowledge. Fast timescale dynamics (ps–ns) were equivalent for both proteins, but suggested exchange events for some residues. Even though most of the intermediate dynamics (μs–ms) occurred at a similar region for both proteins, the specific characteristics are very different. A minor population detected in the dispersion experiments could be associated with the formation of an off-pathway intermediate that protects from fiber formation more efficiently in the germ-line protein. Moreover, we found that the hydrogen bond patterns for both proteins are similar, but the lifetime for the mutant is significantly reduced; as a consequence, there is a decrease in the stability of the tertiary structure that extends throughout the protein and leads to an increase in the propensity to form amyloid fibers. MDPI 2019-08-21 /pmc/articles/PMC6747610/ /pubmed/31438515 http://dx.doi.org/10.3390/ijms20174078 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Maya-Martinez, Roberto
French-Pacheco, Leidys
Valdés-García, Gilberto
Pastor, Nina
Amero, Carlos
Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease
title Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease
title_full Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease
title_fullStr Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease
title_full_unstemmed Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease
title_short Different Dynamics in 6aJL2 Proteins Associated with AL Amyloidosis, a Conformational Disease
title_sort different dynamics in 6ajl2 proteins associated with al amyloidosis, a conformational disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747610/
https://www.ncbi.nlm.nih.gov/pubmed/31438515
http://dx.doi.org/10.3390/ijms20174078
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