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

► We determined the left-handed dimeric structure of transmembrane domain of amyloid precursor protein. ► The dimerization mechanism of APP is important for understanding the molecular mechanism of production of amyloid-β peptide. ► Familial mutations of amyloid precursor protein can affect its late...

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Bibliographic Details
Published in:FEBS letters 2012-06, Vol.586 (12), p.1687-1692
Main Authors: Nadezhdin, Kirill D., Bocharova, Olga V., Bocharov, Eduard V., Arseniev, Alexander S.
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amino Acid Sequence
Amyloid beta-Protein Precursor - chemistry
Amyloid precursor protein
amyloid β-peptide
APP
APP686 – 726 fragment
APPjmtm
Dimerization
dodecylphosphocholine
DPC
heteronuclear single-quantum correlation
HSQC
Humans
Hydrogen Bonding
juxtamembrane
Magnetic Resonance Spectroscopy
Membranes, Artificial
Micelles
Molecular Sequence Data
NMR spectroscopy
NOE
NOE spectroscopy
NOESY
nuclear overhauser effect
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Protein Structure, Quaternary
Protein Structure, Secondary
Spatial structure
transmembrane
Transmembrane domain
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Summary:► We determined the left-handed dimeric structure of transmembrane domain of amyloid precursor protein. ► The dimerization mechanism of APP is important for understanding the molecular mechanism of production of amyloid-β peptide. ► Familial mutations of amyloid precursor protein can affect its lateral dimerization. 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. APPjmtm and APPjmtmbind by comigration in gel electrophoresis (View interaction) APPjmtm and APPjmtmbind by nuclear magnetic resonance (View interaction).
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2012.04.062