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bioRxiv · 10.1101/2020.09.18.304337

Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior

Gisonno, R. A.·Masson, T.·Ramella, N. A.·Barrera, E. E.·Romanowski, V.·Tricerri, M. A.
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Abstract

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 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 the full-length apoA-I model suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its native fold. Following we set up to study the effect of natural mutations on protein conformation and stability. Compared to natural silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of apoA-I 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 and the formation of beta-sheet segments at the C-terminus of apoA-I, giving a possible hint about 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. This information contributes to our understanding of how apoA-I, with its high degree of structural flexibility, maintains a delicate equilibrium between its monomeric 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.

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Gisonno, R. A., Masson, T., Ramella, N. A., Barrera, E. E., Romanowski, V., Tricerri, M. A.. 2020-09-20. Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior. https://doi.org/10.1101/2020.09.18.304337

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