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P4‐228: O‐GlcNAc regulation of hippocampal synaptic plasticity in wild type and 3xTg‐AD mice
Author(s) -
Vosseller Keith,
Skorobogatko Yuliya,
Bryfogle Jared A.,
LaFerla Frank M.,
Vocadlo David J.,
Tallent Melanie
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.694
Subject(s) - long term potentiation , synaptic plasticity , hippocampal formation , synapsin , synapsin i , neuroscience , neurotransmission , schaffer collateral , hippocampus , chemistry , biology , synaptic vesicle , metaplasticity , microbiology and biotechnology , biochemistry , vesicle , receptor , membrane
Directed Mutagenesis. Results: Here we present the crystal structure of the AICD of human APP695 in complex with the C-terminal phosphotyrosine binding domain of Fe65 (Fe65-PTB2) at 2.1 Å resolution. In contrast to classical PTB domain/peptide interactions focusing on the NPX(p)Y consensus motif of the peptide, the AICD/Fe65-PTB2 complex involves two surrounding alpha-helices resulting in a three times enlarged and unique interface. The N-terminal helix of the AICD is capped by threonine 668, which upon phosphorylation regulates complex dissociation and its increased phosphorylation is an important pathologic trait of Alzheimer disease. The crystallographic analysis is complemented by NMR, ITC, and site directed mutagenesis data. Conclusions: The three-dimensional structure of the AICD/Fe65-PTB2 complex gives a detailed view on a central protein complex involved in APP physiology and Alzheimer disease pathology. An impressive number of cell biological, molecular biological, and biochemical data can now be integrated in a solid mechanistic model for complex regulation by the Alzheimer disease relevant phosphorylation of threonine 668 within the AICD. The knowledge of the AICD/Fe65-PTB2 complex structure and of its regulation sets the basis for a new structure based approach in the treatment of Alzheimer disease.