Amyloid-␤ peptide (A␤) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic A␤-Cu 2؉ complex formed via a histidine-bridged dimer, as observed at Cu 2؉ / peptide ratios of >0.6:1 by EPR spectroscopy. The toxicity of the A␤-Cu 2؉ complex to cultured primary cortical neurons was attenuated when either the -or -nitrogen of the imidazole side chains of His were methylated, thereby inhibiting formation of the His bridge. Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation. 31 P magic angle spinning solid-state NMR showed that A␤ and A␤-Cu 2؉ complexes interacted at the surface of a lipid membrane. These findings indicate that the generation of the A␤ toxic species is modulated by the Cu 2؉ concentration and the ability to form an intermolecular His bridge.

Integrin adhesion receptors transduce bidirectional signals across the plasma membrane, with the integrin transmembrane domains acting as conduits in this process. Here, we report the first highresolution structure of an integrin transmembrane domain. To assess the influence of the membrane model system, structure determinations of the 3 integrin transmembrane segment and flanking sequences were carried out in both phospholipid bicelles and detergent micelles. In bicelles, a 30-residue linear R-helix, encompassing residues I693-H772, is adopted, of which I693-I721 appear embedded in the hydrophobic bicelle core. This relatively long transmembrane helix implies a pronounced helix tilt within a typical lipid bilayer, which facilitates the snorkeling of K716's charged side chain out of the lipid core while simultaneously immersing hydrophobic L717-I721 in the membrane. A shortening of bicelle lipid hydrocarbon tails does not lead to the transfer of L717-I721 into the aqueous phase, suggesting that the reported embedding represents the preferred 3 state. The nature of the lipid headgroup affected only the intracellular part of the transmembrane helix, indicating that an asymmetric lipid distribution is not required for studying the 3 transmembrane segment. In the micelle, residues L717-I721 are also embedded but deviate from linear R-helical conformation in contrast to I693-K716, which closely resemble the bicelle structure.

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