Anomalous folding of human apolipoprotein A-I induces amyloidosis

TRICERRI, M. A.; HERNANDEZ, L. B.; FERREIRA, S. T.

Rosario, Santa Fe, Argentina

Congreso; XLII Reunion Anual de la Soc. Argentina de Bioquimica y Biol. Mol.; 2006

Soc. Argentina de Bioquimica y Biol. Mol.

Amyloidosis are characterized by extra cellular deposits of anomalous fibrilar proteins. Human apolipoprotein A-I (apoA-I) is not normally involved within these pathologies. However, one case of severe amyloidosis associated with atherosclerosis was observed when apoA-I shows a deletion of a lysine residue in a central region of the protein (apoA-I Lys107-0). In order to detect the possible factors that induce this anomalous aggregation, we analyzed the folding of the mentioned mutant protein, as compared with wild type apoA-I (wt). Analysis of chemical denaturation and by using hydrostatic pressure show that apoA-I Lys107-0 is more unstable and has a stronger tendency to form b sheet structure as incubation time increases, specially at acidic pH. Under these conditions, mutant denaturation is less cooperative, suggesting intermediate states folding.  Also, this mutant incubated at low pH shows increase in turbidity and binds more tyoflavine T than wt, showing higher yield of fibers as observed by electron microscopy. These results suggest that the anomalous aggregation of apoA-I Lys 107-0, is mediated by intermediate folded states and b sheet conformation, induced by a pH decrease. This situation could be favored by acidosis associated to cardiovascular disease.