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PDBsum entry 5nqh
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Signaling protein
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PDB id
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5nqh
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References listed in PDB file
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Key reference
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Title
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Fe65-Ptb2 dimerization mimics fe65-App interaction.
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Authors
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L.P.Feilen,
K.Haubrich,
P.Strecker,
S.Probst,
S.Eggert,
G.Stier,
I.Sinning,
U.Konietzko,
S.Kins,
B.Simon,
K.Wild.
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Ref.
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Front Mol Neurosci, 2017,
10,
140.
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PubMed id
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Abstract
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Physiological function and pathology of the Alzheimer's disease causing amyloid
precursor protein (APP) are correlated with its cytosolic adaptor Fe65
encompassing a WW and two phosphotyrosine-binding domains (PTBs). The C-terminal
Fe65-PTB2 binds a large portion of the APP intracellular domain (AICD) including
the GYENPTY internalization sequence fingerprint. AICD binding to Fe65-PTB2
opens an intra-molecular interaction causing a structural change and altering
Fe65 activity. Here we show that in the absence of the AICD, Fe65-PTB2 forms a
homodimer in solution and determine its crystal structure at 2.6 Å resolution.
Dimerization involves the unwinding of a C-terminal α-helix that mimics binding
of the AICD internalization sequence, thus shielding the hydrophobic binding
pocket. Specific dimer formation is validated by nuclear magnetic resonance
(NMR) techniques and cell-based analyses reveal that Fe65-PTB2 together with the
WW domain are necessary and sufficient for dimerization. Together, our data
demonstrate that Fe65 dimerizes via its APP interaction site, suggesting that
besides intra- also intermolecular interactions between Fe65 molecules
contribute to homeostatic regulation of APP mediated signaling.
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