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

Abstract

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 Gln686-Lys726 was determined in membrane-mimicking dodecylphosphocholine micelles using high-resolution NMR spectroscopy. The APP membrane-spanning α-helix Lys699-Lys724 self-associates in a left-handed parallel dimer through extended heptad repeat motif I702X3M706X2G709X3A713X2I716X3I720X2I723, whereas the juxtamembrane region Gln686-Val695 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-β peptide. Structured summary of protein interactionsAPPjmtm and APPjmtmbind by comigration in gel electrophoresis (View interaction)APPjmtm and APPjmtmbind by nuclear magnetic resonance (View interaction).