Title |
Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction
|
---|---|
Published in |
Frontiers in Molecular Neuroscience, May 2017
|
DOI | 10.3389/fnmol.2017.00140 |
Pubmed ID | |
Authors |
Lukas P. Feilen, Kevin Haubrich, Paul Strecker, Sabine Probst, Simone Eggert, Gunter Stier, Irmgard Sinning, Uwe Konietzko, Stefan Kins, Bernd Simon, Klemens Wild |
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 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 22 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Bachelor | 4 | 18% |
Student > Ph. D. Student | 4 | 18% |
Student > Master | 3 | 14% |
Student > Doctoral Student | 1 | 5% |
Researcher | 1 | 5% |
Other | 1 | 5% |
Unknown | 8 | 36% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 7 | 32% |
Neuroscience | 6 | 27% |
Immunology and Microbiology | 1 | 5% |
Unknown | 8 | 36% |