Architecture of the Alzheimer’s AβP Ion Channel Pore

Architecture of the Alzheimer’s AβP 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, AβP toxicity can be explained on the basis of harmful ion fluxes across AβP channels. The conformation of AβP 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 AβP. To identify that portion of the AβP molecule making up the conducting pore we have hypothesized that the region of the AβP sequence in the vicinity of the hypothetical pore might interact with complementary regions in the adjacent AβP subunits. We have further hypothesized that an interaction by a peptide segment would block AβP 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 AβP channel. As previously shown for Zn2+ blockade, peptide blockade is also asymmetric. The results also provide additional evidence for the asymmetric insertion of the AβP molecules into lipid membranes, and give support to the concept that rings of histidines line the entry to one side of the AβP pore. The Journal of Membrane Biology Springer Journals

Architecture of the Alzheimer’s AβP Ion Channel Pore

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Copyright © 2004 by Springer-Verlag New York Inc.
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