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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2.
EMBO Rep. 9, 1134-1140 (2008)
Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (A beta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and A beta generation. We determined the crystal structure of the AICD in complex with the C-terminal phospho-tyrosine-binding (PTB) domain of Fe65. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the AICD is capped by threonine T-668, an Alzheimer disease-relevant phosphorylation site involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for unterstanding T-668 phosphorylation-dependent complex regulation at a molecular level. A molecular switch model is proposed.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Alzheimer disease; amyloid precursor protein; APP intracellular domain; Fe65; phosphotyrosine-binding domain
ISSN (print) / ISBN
1469-221X
e-ISSN
1469-3178
Journal
EMBO Reports
Quellenangaben
Volume: 9,
Issue: 11,
Pages: 1134-1140
Publisher
EMBO Press
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)