Solution structures in aqueous SDS micelles of two amyloid beta peptides of A beta(1-28) mutated at the alpha-secretase cleavage site (K16E, K16F)

NMR solution structures are reported for two mutants (K16E, K16F) of the so luble amyloid beta peptide A beta(1-28). The structural effects of these mu tations of a positively charged residue to anionic and hydrophobic residues at the alpha-secretase cleavage site (Lys16-Leu17) were examined in the me mbrane-simulating solvent aqueous SDS micelles. Overall the three-dimension al structures were similar to that for the native A beta(1-28) sequence in that they contained an unstructured N-terminus and a helical C-terminus. Th ese structural elements are similar to those seen in the corresponding regi ons of full-length A beta peptides A beta(1-40) and A beta(1-42), showing t hat the shorter peptides are valid model systems. The K16E mutation, which might be expected to stabilize the macrodipole of the helix, slightly incre ased the helix length (residues 13-24) relative to the K16F mutation, which shortened the helix to between residues 16 and 24. The observed sequence-d ependent control over conformation in this region provides an insight into possible conformational switching roles of mutations in the amyloid precurs or protein from which A beta peptides are derived. In addition, if conforma tional transitions from helix to random coil to sheet precede aggregation o f A beta peptides in vivo, as they do in vitro, the conformation-inducing e ffects of mutations at Lys16 may also influence aggregation and fibril form ation. (C) 2000 Academic Press.