Involvement of 14-3-3 in tubulin instability and impaired axon development is mediated by Tau

14-3-3 proteins act as adapters that exert their function by interacting with their various protein partners. 14-3-3 proteins have been implicated in a variety of human diseases including neurodegenerative diseases. 14-3-3 proteins have recently been reported to be abundant in the neurofibrillary ta...

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Published in:The FASEB journal Vol. 29; no. 10; p. 4133
Main Authors: Joo, Yuyoung, Schumacher, Benjamin, Landrieu, Isabelle, Bartel, Maria, Smet-Nocca, Caroline, Jang, Ahram, Choi, Hee Soon, Jeon, Noo Li, Chang, Keun-A, Kim, Hye-Sun, Ottmann, Christian, Suh, Yoo-Hun
Format: Journal Article
Language:English
Published: United States 01.10.2015
Subjects:
14-3-3 Proteins - chemistry
14-3-3 Proteins - genetics
14-3-3 Proteins - metabolism
Axons - metabolism
Axons - physiology
Binding Sites - genetics
Biomarkers, Tumor - chemistry
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Blotting, Western
Cell Line, Tumor
Cells, Cultured
Crystallography, X-Ray
Cytoskeleton - metabolism
Exoribonucleases - chemistry
Exoribonucleases - genetics
Exoribonucleases - metabolism
Humans
Magnetic Resonance Spectroscopy
Microscopy, Confocal
Models, Molecular
Mutation
Neurites - metabolism
Neurites - physiology
Neurons - metabolism
Phosphorylation
Protein Binding
Protein Structure, Tertiary
Serine - chemistry
Serine - genetics
Serine - metabolism
tau Proteins - chemistry
tau Proteins - genetics
tau Proteins - metabolism
Tauopathies - genetics
Tauopathies - metabolism
Tubulin - metabolism
X-ray crystallography
Alzheimer’s disease
NMR spectroscopy
phosphorylation
protein-protein interactions
ISSN:1530-6860, 1530-6860
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Summary:14-3-3 proteins act as adapters that exert their function by interacting with their various protein partners. 14-3-3 proteins have been implicated in a variety of human diseases including neurodegenerative diseases. 14-3-3 proteins have recently been reported to be abundant in the neurofibrillary tangles (NFTs) observed inside the neurons of brains affected by Alzheimer's disease (AD). These NFTs are mainly constituted of phosphorylated Tau protein, a microtubule-associated protein known to bind 14-3-3. Despite this indication of 14-3-3 protein involvement in the AD pathogenesis, the role of 14-3-3 in the Tauopathy remains to be clarified. In the present study, we shed light on the role of 14-3-3 proteins in the molecular pathways leading to Tauopathies. Overexpression of the 14-3-3σ isoform resulted in a disruption of the tubulin cytoskeleton and prevented neuritic outgrowth in neurons. NMR studies validated the phosphorylated residues pSer214 and pSer324 in Tau as the 2 primary sites for 14-3-3 binding, with the crystal structure of 14-3-3σ in complex with Tau-pSer214 and Tau-pSer324 revealing the molecular details of the interaction. These data suggest a rationale for a possible pharmacologic intervention of the Tau/14-3-3 interaction.
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ISSN:1530-6860
1530-6860
DOI:10.1096/fj.14-265009