This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A major determinant of High Density Lipoprotein (HDL) size is its main protein, Apolipoprotein A-I (apo A-I). Models of apo A-I predict that it contains 10 amphiphilic alpha-helical segments connected by turns. We synthesized four peptides with two 18-residue, amphiphilic alpha-helical segments (Anantharamaiah, G. M. et al., (1985) J. Biol. Chem. 260, 10248-10255) connected by putative turn sequences from apo A-I. 1. Ac-DWLKAFYDKVAEKLKEAFKVEPLRADWLKAFYDKVAEKLKEAF-NH2 2. Ac-DWLKAFYDKVAEKLKEAFGLLPVLEDWLKAFYDKVAEKLKEAF-NH2 3. Ac-DWLKAFYDKVAEKLKEAFKVQPYLDDWLKAFYDKVAEKLKEAF-NH2 4. Ac-DWLKAFYDKVAEKLKEAFNGGARLADWLKAFYDKVAEKLKEAF-NH2 Peptides 1-4 formed precipitates after incubating them at 37 C in 10 mM sodium phosphate, pH 7.60. In contrast to what is expected for typical beta-sheet amyloid fibrils, however, peptides 1 and 2 formed fibrils that did not bind thioflavin T and induced a blue shift in the spectrum of Congo red. Circular dichroism (CD) and Fourier Transform Infrared Spectroscopy (FTIR) of the fibrils from peptides 1 and 2 show significant alpha-helical character. Synchrotron x-ray fiber diffraction on a magnetically aligned sample of 1 has confirmed the alpha-helical character in the fibrils. These data indicate that precipitates or fibrils formed from peptides 1-4 are structurally diverse. Peptides 1 and 2 formed ?-helical fibrils, with helical axes perpendicular to the main fibril axis. In contrast to 1 and 2, only a small amount of precipitate was observed after incubating 3 and 4 at 37 C for 30 days, and these are typical amyloid fibrils by thioflavin T and Congo red binding. These studies indicate that varying turn sequences between longer amphiphilic alpha-helical segments can modulate the structure of fibrils.
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