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Assessing the role of aromatic residues in the amyloid aggregation of human muscle acylphosphatase

Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, 50134, Firenze, Italy

(RECEIVED October 17, 2005; FINAL REVISION January 5, 2006; ACCEPTED January 13, 2006)

Among the many parameters that have been proposed to promote amyloid fibril formation is the -stacking of aromatic residues. We have studied the amyloid aggregation of several mutants of human muscle acylphosphatase in which an aromatic residue was substituted with a non-aromatic one. The aggregation rate was determined using the Thioflavin T test under conditions in which the variants populated initially an ensemble of partially unfolded conformations. Substitutions in aggregation-promoting fragments of the sequence result in a dramatically decreased aggregation rate of the protein, confirming the propensity of aromatic residues to promote this process. Nevertheless, a statistical analysis shows that the measured decrease of aggregation rate following mutation arises predominantly from a reduction of hydrophobicity and intrinsic -sheet propensity. This suggests that aromatic residues favor aggregation because of these factors rather than for their aromaticity.

Keywords: assembly; aggregation mechanism; phenylalanine; molecular recognition; aromatic-aromatic interaction; 2,2,2-trifluoroethanol

Abbreviations: A, amyloid peptideAcP, human muscle acylphosphataseADA2h, activation domain of procarboxypeptidase A2 (human)CD, circular dichroismFTIR, Fourier transform infrared spectroscopySS-NMR, solid state nuclear magnetic resonanceTEM, transmission electron microscopyTFE, 2,2,2-trifluoroethanolThT, Thioflavin T

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