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Fe65-PTB2 dimerization mimics Fe65-APP interaction

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 (AIC...

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Bibliographic Details
Main Authors: Feilen, Lukas Peter (Author) , Haubrich, Kevin (Author) , Stier, Gunter (Author) , Sinning, Irmgard (Author) , Wild, Klemens (Author)
Format: Article (Journal)
Language:English
Published: 11 May 2017
In: Frontiers in molecular neuroscience
Year: 2017, Volume: 10
ISSN:1662-5099
DOI:10.3389/fnmol.2017.00140
Online Access:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.3389/fnmol.2017.00140
Verlag, kostenfrei, Volltext: https://www.frontiersin.org/articles/10.3389/fnmol.2017.00140/full
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Author Notes:Lukas P. Feilen, Kevin Haubrich, Paul Strecker, Sabine Probst, Simone Eggert, Gunter Stier, Irmgard Sinning, Uwe Konietzko, Stefan Kins, Bernd Simon and Klemens Wild
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Summary: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 alpha-helix that mimics binding of the AICD internalization sequence, thus shielding the hydrophobic binding pocket. Specific dimer formation is validated by 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.
Item Description:Gesehen am 07.09.2018
Physical Description:Online Resource
ISSN:1662-5099
DOI:10.3389/fnmol.2017.00140

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