title: Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2.
abstract: Tau protein plays an important role in neuronal physiology and Alzheimer's 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's 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's hot spots of MT interaction bind independently of each other and are differentially affected by phosphorylation.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) , 37077 Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwalbe
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Stefan
authors.initials: S
authors.lastname: Bibow
authors.forename: Valéry
authors.initials: V
authors.lastname: Ozenne
authors.forename: Malene R
authors.initials: MR
authors.lastname: Jensen
authors.forename: Harindranath
authors.initials: H
authors.lastname: Kadavath
authors.forename: Martin
authors.initials: M
authors.lastname: Blackledge
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases