Structural Impact of Tau Phosphorylation at Threonine 231

• Published in: Structure (London) Vol. 23; no. 8; pp. 1448 - 1458
• Main Authors: Schwalbe, Martin, Kadavath, Harindranath, Biernat, Jacek, Ozenne, Valery, Blackledge, Martin, Mandelkow, Eckhard, Zweckstetter, Markus
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 04.08.2015
• Subjects: Amino Acid Sequence; Arginine - chemistry; Arginine - metabolism; Binding Sites; Biochemistry, Molecular Biology; Cloning, Molecular; Escherichia coli - genetics; Escherichia coli - metabolism; Gene Expression; Humans; Life Sciences; Models, Molecular; Molecular Sequence Data; Peptides - chemical synthesis; Peptides - chemistry; Phosphorylation; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Structural Biology; Structure-Activity Relationship; tau Proteins - chemistry; tau Proteins - genetics; Thermodynamics; Threonine - chemistry; Threonine - metabolism
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2015.06.002

Phosphorylation of the microtubule-associated protein Tau influences the assembly and stabilization of microtubules and is deregulated in several neurodegenerative diseases. The high flexibility of Tau, however, has prevented an atomic-level description of its phosphorylation-induced structural changes. Employing an extensive set of distance and orientational restraints together with a novel ensemble calculation approach, we determined conformational ensembles of Tau fragments in the non-phosphorylated state and, when phosphorylated at T231/S235 or T231/S235/S237/S238, four important sites of phosphorylation in Alzheimer disease. Comparison of the molecular ensembles showed that phosphorylation of the regulatory T231 does not perturb the backbone conformation of the proximal microtubule-binding 225KVAVVR230 motif. Instead, phosphorylated T231 selectively engages in a salt bridge with R230 that can compete with the formation of intermolecular salt bridges to tubulin. Our study provides an ensemble description which will be useful for the analysis of conformational transitions in Tau and other intrinsically disordered proteins. [Display omitted] •A novel ensemble calculation approach was developed•Molecular ensembles of phosphorylated Tau fragments were determined•Phosphorylated T231 selectively engages in a salt bridge with R230•Integration of NOE restraints with ensemble calculations are highly useful for IDPs Alzheimer disease-related protein Tau is a phosphoprotein, and a number of different residues are subject to phosphorylation. Schwalbe et al. develop a molecular ensemble approach and use it to reveal an atomic-level description of the phosphorylation-induced structural changes in Tau phosphorylated at Thr231.