The interactome of the amyloid β precursor protein family members is shaped by phosphorylation of their intracellular domains

Robert Tamayev,Dawang Zhou,Luciano D'Adamio

doi:10.1186/1750-1326-4-28

Robert Tamayev, Dawang Zhou + Show 1 more

Open Access

https://doi.org/10.1186/1750-1326-4-28

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Abstract

BackgroundBrain tissue from patients with Alzheimer's disease has shown an increase of phosphorylation of Tyr-682, located on the conserved Y682ENPTY motif, and Thr-668 residues, both in the intracellular domain (AID) of amyloid β precursor protein (APP), although the role of these two residues is not yet known.ResultsHere, we report that the phosphorylation status of Tyr-682, and in some cases Thr-668, shapes the APP interactome. It creates a docking site for SH2-domain containing proteins, such as ShcA, ShcB, ShcC, Grb7, Grb2, as well as adapter proteins, such as Crk and Nck, that regulate important biological processes, cytosolic tyrosine kinases, such as Abl, Lyn and Src, which regulate signal transduction pathways, and enzymes that control phosphatidylinositols levels and signaling, such as PLC-γ. At the same time, it either reduces (like for JIP1, NUMB, NUMBL and ARH) or abolishes (like for Fe65, Fe65L1 and Fe65L2) binding of other APP interactors. Phosphorylation of Thr-668, unlike Tyr-682, does not seem to affect APP's ability to interact with the various proteins, with Pin1 and X11 being the exclusions. We also found that there are some differences between the interactions to AID and to ALID1 and ALID2, its two homologues.ConclusionOur data indicates that APP can regulate diverse cellular processes and that, vice versa, a network of signaling events can impact APP processing. Our results also suggest that phosphorylation of the APP Intracellular Domain will dramatically shape the APP interactome and, consequently, will regulate APP processing, APP transport and APP/AID-mediated functions.

Highlights

Brain tissue from patients with Alzheimer's disease has shown an increase of phosphorylation of Tyr-682, located on the conserved Y682ENPTY motif, and Thr-668 residues, both in the intracellular domain (AID) of amyloid β precursor protein (APP), the role of these two residues is not yet known
This is followed by an intramembranous proteolytic event, where COOH-terminal fragment of 99 amino acids (C99) is cleaved by the γ-secretase to produce amyloid β peptides (Aβ) peptides plus the APP intracellular Domain (AID/AICD)
Αsecretase cleaves APP in the Aβ sequence into sAPPα and the membrane bound COOH-terminal fragment of 83 amino acids (C83), which is cleaved by γ-secretase into P3 and APP intracellular domain (AID)

Summary

Introduction

Brain tissue from patients with Alzheimer's disease has shown an increase of phosphorylation of Tyr-682, located on the conserved Y682ENPTY motif, and Thr-668 residues, both in the intracellular domain (AID) of amyloid β precursor protein (APP), the role of these two residues is not yet known. APP is cleaved by β-secretase, [3] releasing the ectodomain (sAPPβ), while the COOH-terminal fragment of 99 amino acids (C99) remains membrane bound. This is followed by an intramembranous proteolytic event, where C99 is cleaved by the γ-secretase to produce Aβ peptides plus the APP intracellular Domain (AID/AICD). Αsecretase cleaves APP in the Aβ sequence into sAPPα and the membrane bound COOH-terminal fragment of 83 amino acids (C83), which is cleaved by γ-secretase into P3 (the COOH-terminal Aβ segment) and AID. Molecular Neurodegeneration 2009, 4:28 http://www.molecularneurodegeneration.com/content/4/1/28 numbering is according to the APP695 neuronal isoform) releasing the COOH-terminal 31 amino acids of APP (C31) and the membrane bound APPΔC31. AID can modulate cell death [7,8,9,10,11], gene transcription [8,12,13,14,15,16,17,18,19,20] and Ca++ homeostasis [21,22]

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