Phosphorylation of Human Tau Protein by Microtubule Affinity-Regulating Kinase 2

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• 作者：Martin Schwalbe ; Jacek Biernat ; Stefan Bibow ; Val茅ry Ozenne ; Malene R. Jensen ; Harindranath Kadavath ; Martin Blackledge ; Eckhard Mandelkow ; Markus Zweckstetter
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：December 17, 2013
• 年：2013
• 卷：52
• 期：50
• 页码：9068-9079
• 全文大小：751K
• 年卷期：v.52,no.50(December 17, 2013)
• ISSN：1520-4995

文摘

Tau protein plays an important role in neuronal physiology and Alzheimer鈥檚 neurodegeneration. Its abilities to aggregate abnormally, to bind to microtubules (MTs), and to promote MT assembly are all influenced by phosphorylation. Phosphorylation of serine residues in the KXGS motifs of Tau鈥檚 repeat domain, crucial for MT interactions and aggregation, is facilitated most efficiently by microtubule-associated protein/microtubule affinity-regulating kinases (MARKs). Here we applied high-resolution nuclear magnetic resonance analysis to study the kinetics of phosphorylation of Tau by MARK2 and its impact on the structure and microtubule binding of Tau. We demonstrate that MARK2 binds to the N-terminal tail of Tau and selectively phosphorylates three major and five minor serine residues in the repeat domain and C-terminal tail. Structural changes induced by phosphorylation of Tau by MARK2 are highly localized in the proximity of the phosphorylation site and do not affect the global conformation, in contrast to phosphorylation in the proline-rich region. Furthermore, single-residue analysis of binding of Tau to MTs provides support for a model in which Tau鈥檚 hot spots of MT interaction bind independently of each other and are differentially affected by phosphorylation.