Architecture of the Alzheimer's A beta P ion channel pore.
We have proposed that the cytotoxic action of Alzheimer's amyloid beta protein might be initiated by the interaction with the neuronal cell membrane, and subsequent formation of toxic ion channels. Consequently, A beta P toxicity can be explained on the basis of harmful ion fluxes across A beta P channels. The conformation of A beta P in membranes is not known. However, several models suggests that a transmembrane annular polymeric structure is responsible for the ion channel properties of the membrane-bound A beta P. To identify that portion of the A beta P molecule making up the conducting pore we have hypothesized that the region of the A beta P sequence in the vicinity of the hypothetical pore might interact with complementary regions in the adjacent A beta P subunits. We have further hypothesized that an interaction by a peptide segment would block A beta P conductance. To test this hypothesis we synthesized peptides that encompass the histidine dyad (H-H) previously hypothesized to line the pore. We report here that peptides designed to most closely match the proposed pore are, in fact, the most effective at blocking ion currents through the membrane-incorporated A beta P channel. As previously shown for Zn(2+) blockade, peptide blockade is also asymmetric. The results also provide additional evidence for the asymmetric insertion of the A beta P molecules into lipid membranes, and give support to the concept that rings of histidines line the entry to one side of the A beta P pore.
Arispe
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Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services, University School of Medicine, USUHS, Bethesda, MD, 20814, USA. narispe@usuhs.mil
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D004553:Electric Conductivity; D006639:Histidine / Q000737:chemistry*; D015640:Ion Channel Gating; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008564:Membrane Potentials; D008567:Membranes, Artificial; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D010539:Permeability; D016062:Porosity; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008081:Liposomes; D008567:Membranes, Artificial; D010455:Peptides; D006639:Histidine