5NQH

Structure of the human Fe65-PTB2 homodimer

Summary for 5NQH

• Entry DOI: 10.2210/pdb5nqh/pdb
• Descriptor: Amyloid beta A4 precursor protein-binding family B member 1, SULFATE ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: alzheimers disease, phosphotyrosine-binding (ptb) domain, signaling protein, homodimerization
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane: O00213
• Total number of polymer chains: 4
• Total formula weight: 62875.61

Authors

Feilen, L.P.,Haubrich, K.,Sinning, I.,Konietzko, U.,Kins, S.,Simon, B.,Wild, K. (deposition date: 2017-04-20, release date: 2017-05-03, Last modification date: 2024-01-17)

Primary citation

Feilen, L.P.,Haubrich, K.,Strecker, P.,Probst, S.,Eggert, S.,Stier, G.,Sinning, I.,Konietzko, U.,Kins, S.,Simon, B.,Wild, K.
Fe65-PTB2 Dimerization Mimics Fe65-APP Interaction.
Front Mol Neurosci, 10:140-140, 2017

PubMed 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.

PubMed: 28553201
DOI: 10.3389/fnmol.2017.00140

Experimental method

X-RAY DIFFRACTION (2.6 Å)