Mapping the Structural Transition in an Amyloidogenic Apolipoprotein A-I†

The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIOWA) leads to the formation of β-secondary structure rich amyloid fibrils in vivo. Here we show that full-length apoA-IIOWA has a decreased lipid-binding capability, an increased amino-terminal sensitivity to protease, and a propensity to form annular protofibrils visible by electron microscopy. The molecular basis for the conversion of apolipoprotein A-I to a proamyloidogenic form was examined by electron paramagnetic resonance spectroscopy. Our recent findings [Lagerstedt, J. O., Budamagunta, M. S., Oda, M. N., and Voss, J. C. (2007) J. Biol. Chem. 282, 9143−9149] indicate that Gly26 in the native apoprotein separates a preceding β-strand structure (residues 20−25) from a downstream largely α-helical region. The current study demonstrates that the G26R variant promotes a structural transition of positions 27−56 to a mixture of coil and β-strand secondary structure. Microscopy and staining by amyloidophilic dyes suggest that this alt...