Affiliations: [a] Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Greece | [b] Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece | [c] Institute of Molecular Biology and Genetics, Biomedical Sciences Research Centre Alexander Fleming, Athens, Greece
Correspondence:
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Correspondence to: Dr. Spiros Efthimiopoulos, Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, 157 84 Panepistimiopolis, Ilisia, Athens, Greece. Tel.: +30 210 7274 890; Fax: +30 210 7274 635; E-mail: [email protected].
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.
Keywords: Alzheimer's disease, amyloid-β protein precursor (AβPP), homer, protein interactions
