RESUMEN
Amyloid-ß protein precursor (AßPP) metabolism and the accumulation of its derivative amyloid-ß (Aß) 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 Aß are not clear but emphasis has been given in the role of AßPP protein interactions that regulate its processing and offer a means to manipulate Aß production. We have previously shown that AßPP interacts with members of the Homer protein family, which leads to inhibition of Aß generation. Herein, we studied the structural parameters of AßPP/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 AßPP 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 AßPP, possibly underlying our recent work suggesting that calcium signaling also regulates the interaction. Our results show that the regulation of AßPP/Homer3 interaction might be critical in the context of Alzheimer's disease pathology as a novel target for regulating AßPP function and metabolism.