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Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State

Beta-2 microglobulin (β2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of β2m, D76N, presents a higher amyloidogenic propensity compared to the wild type c...

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Autores principales: Visconti, Lorenzo, Malagrinò, Francesca, Broggini, Luca, De Luca, Chiara Maria Giulia, Moda, Fabio, Gianni, Stefano, Ricagno, Stefano, Toto, Angelo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359115/
https://www.ncbi.nlm.nih.gov/pubmed/30669253
http://dx.doi.org/10.3390/ijms20020396
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author Visconti, Lorenzo
Malagrinò, Francesca
Broggini, Luca
De Luca, Chiara Maria Giulia
Moda, Fabio
Gianni, Stefano
Ricagno, Stefano
Toto, Angelo
author_facet Visconti, Lorenzo
Malagrinò, Francesca
Broggini, Luca
De Luca, Chiara Maria Giulia
Moda, Fabio
Gianni, Stefano
Ricagno, Stefano
Toto, Angelo
author_sort Visconti, Lorenzo
collection PubMed
description Beta-2 microglobulin (β2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of β2m, D76N, presents a higher amyloidogenic propensity compared to the wild type counterpart. Since the three-dimensional structure of the protein is essentially unaffected by the mutation, the increased aggregation propensity of D76N has been generally ascribed to its lower thermodynamic stability and increased dynamics. In this study we compare the equilibrium unfolding and the aggregation propensity of wild type β2m and D76N variant at different experimental conditions. Our data revealed a surprising effect of the D76N mutation in the residual structure of the denatured state, which appears less compact than that of the wild type protein. A careful investigation of the structural malleability of the denatured state of wild type β2m and D76N pinpoint a clear role of the denatured state in triggering the amyloidogenic propensity of the protein. The experimental results are discussed in the light of the previous work on β2m and its role in disease.
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spelling pubmed-63591152019-02-06 Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State Visconti, Lorenzo Malagrinò, Francesca Broggini, Luca De Luca, Chiara Maria Giulia Moda, Fabio Gianni, Stefano Ricagno, Stefano Toto, Angelo Int J Mol Sci Article Beta-2 microglobulin (β2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of β2m, D76N, presents a higher amyloidogenic propensity compared to the wild type counterpart. Since the three-dimensional structure of the protein is essentially unaffected by the mutation, the increased aggregation propensity of D76N has been generally ascribed to its lower thermodynamic stability and increased dynamics. In this study we compare the equilibrium unfolding and the aggregation propensity of wild type β2m and D76N variant at different experimental conditions. Our data revealed a surprising effect of the D76N mutation in the residual structure of the denatured state, which appears less compact than that of the wild type protein. A careful investigation of the structural malleability of the denatured state of wild type β2m and D76N pinpoint a clear role of the denatured state in triggering the amyloidogenic propensity of the protein. The experimental results are discussed in the light of the previous work on β2m and its role in disease. MDPI 2019-01-18 /pmc/articles/PMC6359115/ /pubmed/30669253 http://dx.doi.org/10.3390/ijms20020396 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
Visconti, Lorenzo
Malagrinò, Francesca
Broggini, Luca
De Luca, Chiara Maria Giulia
Moda, Fabio
Gianni, Stefano
Ricagno, Stefano
Toto, Angelo
Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
title Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
title_full Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
title_fullStr Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
title_full_unstemmed Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
title_short Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
title_sort investigating the molecular basis of the aggregation propensity of the pathological d76n mutant of beta-2 microglobulin: role of the denatured state
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359115/
https://www.ncbi.nlm.nih.gov/pubmed/30669253
http://dx.doi.org/10.3390/ijms20020396
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