Fe65-PTB2 dimerization mimics Fe65-APP interaction

• Verfasst von: Feilen, Lukas [VerfasserIn]
• Verfasst von: Haubrich, Kevin [VerfasserIn]
• Verfasst von: Stier, Gunter [VerfasserIn]
• Verfasst von: Sinning, Irmgard [VerfasserIn]
• Verfasst von: Wild, Klemens [VerfasserIn]
• Titel: Fe65-PTB2 dimerization mimics Fe65-APP interaction
• Verf.angabe: Lukas P. Feilen, Kevin Haubrich, Paul Strecker, Sabine Probst, Simone Eggert, Gunter Stier, Irmgard Sinning, Uwe Konietzko, Stefan Kins, Bernd Simon and Klemens Wild
• Fussnoten: Gesehen am 07.09.2018
• Titel Quelle: Enthalten in: Frontiers in molecular neuroscience
• Jahr Quelle: 2017
• Band/Heft Quelle: 10(2017) Artikel-Nummer 140, 12 Seiten
• ISSN Quelle: 1662-5099
• DOI: doi:10.3389/fnmol.2017.00140
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1580776639

Abstract

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.