Artículo
Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior
Gisonno, Romina Antonela
; Masson, Tomas
; Ramella, Nahuel
; Barrera Guisasola, Exequiel Ernesto
; Romanowski, Victor
; Tricerri, Maria Alejandra
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Fecha de publicación:
08/2021
Editorial:
Wiley-liss, div John Wiley & Sons Inc.
Revista:
Proteins: Structure, Function And Genetics
ISSN:
0887-3585
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Apolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural consequences 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 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 that among the four amyloidogenic regions described for human apoA-I, only two (APR1 and APR4) are evolutionary conserved across different species of Sarcopterygii. Moreover, stability analysis carried out with the FoldX engine showed that APR1 contributes to the marginal stability of apoA-I. Structural properties of full-length apoA-I models suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its native fold. Compared to silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of amyloid mutations showed evidence of a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the alpha-helix bundle with the concomitant exposure of APR1 to the solvent, suggesting an insight into the early steps involved in its aggregation. 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 this region.
Palabras clave:
AGGREGATION-PRONO
,
APOA-I
,
CONSERVED
,
FLEXIBILITY
,
STABILITY
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Licencia
Identificadores
Colecciones
Articulos(INIBIOLP)
Articulos de INST.DE INVEST.BIOQUIMICAS DE LA PLATA
Articulos de INST.DE INVEST.BIOQUIMICAS DE LA PLATA
Citación
Gisonno, Romina Antonela; Masson, Tomas; Ramella, Nahuel; Barrera Guisasola, Exequiel Ernesto; Romanowski, Victor; et al.; Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior; Wiley-liss, div John Wiley & Sons Inc.; Proteins: Structure, Function And Genetics; 90; 1; 8-2021; 258-269
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