Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment

Some pathogenic mutations associated with Alzheimer's disease are thought to affect structural-dynamic properties and the lateral dimerization of amyloid precursor protein (APP) in neuron membrane. Dimeric structure of APP transmembrane fragment Gln(686)-Lys(726) was determined in membrane-mimicking dodecylphosphocholine micelles using high-resolution NMR spectroscopy. The APP membrane-spanning alpha-helix Lys(699)-Lys(724) self-associates in a left-handed parallel dimer through extended heptad repeat motif I(702)X(3)M(706)X(2)G(709)X(3)A(713)X(2)I(716)X(3)I(720)X(2)I(723), whereas the juxta-membrane region Gln(686)-Val(695) constitutes the nascent helix, also sensing the dimerization. The dimerization mechanism of APP transmembrane domain has been described at atomic resolution for the first time and is important for understanding molecular events of APP sequential proteolytical cleavage resulting in amyloid-beta peptide. Structured summary of protein interactions: APPjmtm and APPjmtm bind by comigration in gel electrophoresis (View interaction) APPjmtm and APPjmtm bind by nuclear magnetic resonance (View interaction). (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.