The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function

Alessia P M Barbagallo, Zilai Wang, Hui Zheng, Luciano D'Adamio

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. Methodology/Principal Findings: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr668 is replaced by an Ala (T668A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T668A allele into the APLP2 knockout background showed that mutation of Thr668 does not cause a defective phenotype. Notably, the T668A mutant APP is able to bind Mint1. Conclusions/Significance: Our results argue against an important role of the Thr668 residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved in those APP-mediated functions that prevent (NMJ) defects and early lethality in APLP2 null mice.

Original languageEnglish (US)
Article numbere18006
JournalPLoS One
Volume6
Issue number3
DOIs
StatePublished - 2011

Fingerprint

Protein Precursors
Amyloid beta-Protein Precursor
Threonine
amyloid
threonine
proteins
Neuromuscular Junction
Alzheimer Disease
Proteins
Alleles
Defects
Alzheimer disease
Staphylococcal Protein A
Phosphorylation
Synapses
pathogenesis
Binding Sites
alleles
Phenotype
Amino Acids

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function. / Barbagallo, Alessia P M; Wang, Zilai; Zheng, Hui; D'Adamio, Luciano.

In: PLoS One, Vol. 6, No. 3, e18006, 2011.

Research output: Contribution to journalArticle

Barbagallo, Alessia P M ; Wang, Zilai ; Zheng, Hui ; D'Adamio, Luciano. / The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function. In: PLoS One. 2011 ; Vol. 6, No. 3.
@article{2996a2a752764f62a8f6b1b38fa5cfc3,
title = "The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function",
abstract = "Background: Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. Methodology/Principal Findings: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr668 is replaced by an Ala (T668A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T668A allele into the APLP2 knockout background showed that mutation of Thr668 does not cause a defective phenotype. Notably, the T668A mutant APP is able to bind Mint1. Conclusions/Significance: Our results argue against an important role of the Thr668 residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved in those APP-mediated functions that prevent (NMJ) defects and early lethality in APLP2 null mice.",
author = "Barbagallo, {Alessia P M} and Zilai Wang and Hui Zheng and Luciano D'Adamio",
year = "2011",
doi = "10.1371/journal.pone.0018006",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function

AU - Barbagallo, Alessia P M

AU - Wang, Zilai

AU - Zheng, Hui

AU - D'Adamio, Luciano

PY - 2011

Y1 - 2011

N2 - Background: Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. Methodology/Principal Findings: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr668 is replaced by an Ala (T668A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T668A allele into the APLP2 knockout background showed that mutation of Thr668 does not cause a defective phenotype. Notably, the T668A mutant APP is able to bind Mint1. Conclusions/Significance: Our results argue against an important role of the Thr668 residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved in those APP-mediated functions that prevent (NMJ) defects and early lethality in APLP2 null mice.

AB - Background: Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. Methodology/Principal Findings: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr668 is replaced by an Ala (T668A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T668A allele into the APLP2 knockout background showed that mutation of Thr668 does not cause a defective phenotype. Notably, the T668A mutant APP is able to bind Mint1. Conclusions/Significance: Our results argue against an important role of the Thr668 residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved in those APP-mediated functions that prevent (NMJ) defects and early lethality in APLP2 null mice.

UR - http://www.scopus.com/inward/record.url?scp=79952952445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952952445&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0018006

DO - 10.1371/journal.pone.0018006

M3 - Article

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e18006

ER -