title: Threonine 576 residue of amyloid-β precursor protein regulates its trafficking and processing.
abstract: Deposition of amyloid-β (Aβ) in the brain is the main culprit of Alzheimer's disease (AD). Aβ is derived from sequential proteolytic cleavage of amyloid-β precursor protein (APP). Newly synthesized APP is transported from endoplasmic reticulum to the plasma membrane via trans-Golgi network (TGN) after post-translational modification including N- and O-glycosylation. APP is internalized through clathrin-dependent endocytosis from the plasma membrane to the early endosomes. In this study, we investigated the regulation of APP trafficking and processing by mutating three threonine residues known as O-glycosylation sites. We separately mutated three threonine residues of APP695 into alanines (T291A, T292A, and T576A) and expressed them in HeLa cells. Among these APP mutants, only T576A mutant showed reduced cell surface levels, indicating this residue regulates its trafficking. We also confirmed that trafficking from TGN to the plasma membrane was decreased in T576A mutant. Consistent with these observations, T576A mutant accumulated in the early endosomes, and the secreted Aβ level was increased. Thus, these results indicate that threonine 576 residue of APP regulates its trafficking and processing.
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Chun
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Oh-Hoon
authors.initials: OH
authors.lastname: Kwon
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Hyun Geun
authors.initials: HG
authors.lastname: Oh
authors.affiliation: Department of Pathology and Cell Biology, and Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Department of Pathology and Cell Biology, and Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Laura Beth
authors.initials: LB
authors.lastname: McIntire
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Myoung Kyu
authors.initials: MK
authors.lastname: Park
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea. Electronic address: schung@skku.edu.
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Chung
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D015388:Organelles / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D013912:Threonine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D013912:Threonine
keywords: Alzheimer's disease; Amyloid; Amyloid-β protein precursor