Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

GISONNO, ROMINA A.; MASSON, TOMAS; RAMELLA, NAHUEL A.; BARRERA, EXEQUIEL E.; ROMANOWSKI, VÍCTOR; TRICERRI, M. ALEJANDRA

PROTEINS: STRUCTURE, FUNCTION AND GENETICS

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2021

0887-3585

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 amyloidpathology. Although several studies have tackled the biophysical and structural consequences introduced by these mutations, there is little information addressing therelationship between the evolutionary and structural features that contribute to theamyloid behavior of apoA-I. We combined evolutionary studies, in silico mutagenesisand molecular dynamics (MD) simulations to provide a comprehensive analysis of theconservation and pathogenic role of the aggregation-prone regions (APRs) present inapoA-I. Sequence analysis demonstrated that among the four amyloidogenic regionsdescribed for human apoA-I, only two (APR1 and APR4) are evolutionary conservedacross different species of Sarcopterygii. Moreover, stability analysis carried out withthe 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 avoidedby placing APRs into highly packed and rigid portions of its native fold. Compared tosilent 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 thealpha-helix bundle with the concomitant exposure of APR1 to the solvent, suggestingan insight into the early steps involved in its aggregation. Our findings highlight APR1as a relevant component for apoA-I structural integrity and emphasize a destabilizingeffect of amyloid variants that leads to the exposure of this region.