title: Structural and regulatory elements of the interaction between amyloid-β protein precursor and Homer3.
abstract: Amyloid-β protein precursor (AβPP) metabolism and the accumulation of its derivative amyloid-β (Aβ) peptide in senile plaques have been considered key players in the development of Alzheimer's disease (AD). However, the mechanisms underlying the generation and the deposition of Aβ are not clear but emphasis has been given in the role of AβPP protein interactions that regulate its processing and offer a means to manipulate Aβ production. We have previously shown that AβPP interacts with members of the Homer protein family, which leads to inhibition of Aβ generation. Herein, we studied the structural parameters of AβPP/Homer3 interaction by analyzing the sequences and domains that play a role in the formation of the complex. We found that the cytoplasmic tail of AβPP is necessary for the interaction. Regarding Homer3, we report that both the EVH1 protein interacting domain and the polymerization coiled coil domain are essential for the complex assembly. Importantly, phosphorylation of Homers at certain serine residues seems to enhance the interaction with AβPP, possibly underlying our recent work suggesting that calcium signaling also regulates the interaction. Our results show that the regulation of AβPP/Homer3 interaction might be critical in the context of Alzheimer's disease pathology as a novel target for regulating AβPP function and metabolism.
authors.affiliation: Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Greece Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Elli
authors.initials: E
authors.lastname: Kyratzi
authors.affiliation: Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Greece Institute of Molecular Biology and Genetics, Biomedical Sciences Research Centre Alexander Fleming, Athens, Greece.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Liakos
authors.affiliation: Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Papadogiannaki
authors.affiliation: Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Greece.
authors.forename: Spiros
authors.initials: S
authors.lastname: Efthimiopoulos
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D000072233:Homer Scaffolding Proteins; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D050436:Regulatory Elements, Transcriptional / Q000502:physiology*; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; C000606616:HOMER3 protein, human; D000072233:Homer Scaffolding Proteins
keywords: Alzheimer's disease; amyloid-β protein precursor (AβPP); homer; protein interactions