Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 43, Pages 33435-33444Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.149419
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- Region Nord-Pas de Calais (France)
- CNRS
- University of Lille 1
- Institut Pasteur de Lille
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Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-beta peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated Tau protein. Tau is mostly found in a hyperphosphorylated form in these tangles. Glycogen synthase kinase 3 beta (GSK3 beta) is a proline-directed kinase generally considered as one of the major players that (hyper)phosphorylates Tau. The kinase phosphorylates mainly (Ser/Thr)-Pro motifs and is believed to require a priming activity by another kinase. Here, we use an in vitro phosphorylation assay and NMR spectroscopy to characterize in a qualitative and quantitative manner the phosphorylation of Tau by GSK3 beta. We find that three residues can be phosphorylated (Ser-396, Ser-400, and Ser-404) by GSK3 beta alone, without priming. Ser-404 is essential in this process, as its mutation to Ala prevents all activity of GSK3 beta. However, priming enhances the catalytic efficacy of the kinase, as initial phosphorylation of Ser-214 by the cAMP-dependent protein kinase (PKA) leads to the rapid modification by GSK3 beta of four regularly spaced additional sites. Because the regular incorporation of negative charges by GSK3 beta leads to a potential parallel between phospho-Tau and heparin, we investigated its interaction with the heparin/low density lipoprotein receptor binding domain of human apolipoprotein E. We indeed observed an interaction between the GSK3 beta-promoted regular phospho-pattern on Tau and the apolipoprotein E fragment but none in the absence of phosphorylation or the presence of an irregular phosphorylation pattern by the prolonged activity of PKA. Apolipoprotein E is therefore able to discriminate and interact with specific phosphorylation patterns of Tau.
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