SOLUTION STRUCTURE OF AMYLOID BETA-PEPTIDE(1-40) IN A WATER-MICELLE ENVIRONMENT - IS THE MEMBRANE-SPANNING DOMAIN WHERE WE THINK IT IS

The three-dimensional solution structure of the 40 residue amyloid bet a-peptide, A beta(1-40), has been determined using NMR spectroscopy at pH 5.1, in aqueous sodium dodecyl sulfate (SDS) micelles, In this env ironment, which simulates to some extent a water-membrane medium, the peptide is unstructured between residues 1 and 14 which are mainly pol ar and likely solvated by water. However, the rest of the protein adop ts an alpha-helical conformation between residues 15 and 36 with a kin k or hinge at 25-27. This largely hydrophobic region is likely solvate d by SDS. Based on the derived structures, evidence is provided in sup port of a possible new location for the transmembrane domain of A beta within the amyloid precursor protein (APP). Studies between pH 4.2 an d 7.9 reveal a pH-dependent helix-coil conformational switch. At the l ower pH values, where the carboxylate residues are protonated, the hel ix is uncharged, intact, and lipid-soluble. As the pH increases above 6.0, part of the helical region (15-24) becomes less structured, parti cularly near residues E22 and D23 where deprotonation appears to facil itate unwinding of the helix. This pH-dependent unfolding to a random coil conformation precedes any tendency of this peptide to aggregate t o a beta-sheet as the pH increases. The structural biology described h erein for A beta(1-40) suggests that (i) the C-terminal two-thirds of the peptide is an alpha-helix in membrane-like environments, (ii) depr otonation of two acidic amino acids in the helix promotes a helix-coil conformational transition that precedes aggregation, (iii) a mobile h inge exists in the helical region of A beta(1-40) and this may be rele vant to its membrane-inserting properties and conformational rearrange ments, and (iv) the location of the transmembrane domain of amyloid pr ecursor proteins may be different from that accepted in the Literature . These results may provide new insight to the structural properties o f amyloid beta-peptides of relevance to Alzheimer's disease.