Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior

Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport mediated by the high-density lipoprotein (HDL) particles. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and struct...

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Autores principales: Gisonno, Romina Antonela, Masson, Tomás, Ramella, Nahuel Alberto, Barrera, Exequiel E., Romanowski, Víctor, Tricerri, María Alejandra
Formato: Articulo Preprint
Lenguaje:Inglés
Publicado: 2020
Materias:
Biología
Bioquímica
Aggregation
Amyloidosis
Apolipoprotein
Evolutionary-conserved
Variants
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/124660
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-124660
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
Bioquímica
Aggregation
Amyloidosis
Apolipoprotein
Evolutionary-conserved
Variants
spellingShingle Biología
Bioquímica
Aggregation
Amyloidosis
Apolipoprotein
Evolutionary-conserved
Variants
Gisonno, Romina Antonela
Masson, Tomás
Ramella, Nahuel Alberto
Barrera, Exequiel E.
Romanowski, Víctor
Tricerri, María Alejandra
Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior
topic_facet Biología
Bioquímica
Aggregation
Amyloidosis
Apolipoprotein
Evolutionary-conserved
Variants
description Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport mediated by the high-density lipoprotein (HDL) particles. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural impacts introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA-I. We combined evolutionary studies, in silico saturation mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation-prone regions (APRs) present in apoA-I. Sequence analysis demonstrated the pervasive conservation of an APR, designated here APR1, within the N-terminal ɑ-helix bundle. Moreover, stability analysis carried out with the FoldX engine showed that this motif contributes to the marginal stability of apoA-I. Structural properties of the full-length apoA-I model suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its structure. Compared to HDL-deficiency or natural silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of apoA-I point mutations associated with amyloid pathologies were found to show a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the ɑ-helix bundle and the occurrence of β-strand secondary elements at the C-terminus of apoA-I. Our findings highlight APR1 as a relevant component for apoA-I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of APRs. This information contributes to our understanding of how apoA-I, with its high degree of structural flexibility, maintains a delicate equilibrium between its native structure and intrinsic tendency to form amyloid aggregates. In addition, our stability measurements could be used as a proxy to interpret the structural impact of new mutations affecting apoA-I.
format Articulo
Preprint
author Gisonno, Romina Antonela
Masson, Tomás
Ramella, Nahuel Alberto
Barrera, Exequiel E.
Romanowski, Víctor
Tricerri, María Alejandra
author_facet Gisonno, Romina Antonela
Masson, Tomás
Ramella, Nahuel Alberto
Barrera, Exequiel E.
Romanowski, Víctor
Tricerri, María Alejandra
author_sort Gisonno, Romina Antonela
title Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior
title_short Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior
title_full Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior
title_fullStr Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior
title_full_unstemmed Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior
title_sort evolutionary and structural constraints influencing apolipoprotein a-i amyloid behavior
publishDate 2020
url http://sedici.unlp.edu.ar/handle/10915/124660
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