Influence of phosphorylation state on the structure of a Tau protein helical fragment: A molecular dynamics simulation study. — ASN Events
  1. Schedule
  2. Session Twelve - Poster Session D including Happy Hour & Trade Display
  3. Influence of phosphorylation state on the structure of a Tau protein helical fragment: A molecular dynamics simulation study.

Influence of phosphorylation state on the structure of a Tau protein helical fragment: A molecular dynamics simulation study. (#403)

Ricardo L. Mancera 1 , Albert J. Lyons 1 , Neha S. Gandhi 1
  1. School of Biomedical Sciences, Curtin University, Perth, WA, Australia

Tau is a highly soluble microtubule-associated protein (MAP) and its hyperphopshorylation is linked to several tauopathies. The role of Tau phosphorylation and dephosphorylation is very poorly understood during microtubule (MT) stabilization as well as its role in the formation of neurofibrillary tangles in Alzheimer disease (AD). The presence of many hyperphosphorylation sites in the proline-rich domain (PRR) of the Tau protein suggests that the proline-rich domain may be important in phosphorylation-induced conformational changes. Phosphorylation at Thr231/Ser235 in the PRR of the Tau protein abolishes its capacity to polymerize tubulin into MT. In this study, we address the structural impact of phosphorylation of the Tau protein by molecular dynamics (MD) simulations of a functional fragment (Lys225-Met250). The Tau protein fragment was phosphorylated on Thr231 and/or Ser235. Previous experimental studies based on circular dichroism spectroscopy and the measurement of NMR coupling constants have suggested the stabilization of a type II polyproline helix upon phosphorylation for two peptides (Val229-Ser238 and Val229-Lys240)1, whereas a Tau protein peptide (Lys224-Lys240) with two phosphorylated residues, pThr231 and pSer235, was reported to have a type I (or III) β-turn topology in the phosphorylated peptide.2 Salt bridges, hydrogen bonding and secondary structures were monitored during MD simulations and it was found that phosphorylation of the Thr231 and Ser235 residues stabilizes a short α-helix that runs from Ser237 until the first MT binding repeat, in agreement with NMR data.3

  1. Bielska AA and Zondlo NJ. Hyperphosphorylation of tau induces local polyproline II helix. Biochemistry. 2006;45(17):5527-37.
  2. Daly NL, Hoffmann R, Otvos L,Jr and Craik DJ. Role of phosphorylation in the conformation of tau peptides implicated in Alzheimer's disease. Biochemistry 2000; 39: 9039–9046.
  3. Sibille N, Huvent I, Fauquant C, Verdegem D, Amniai L, Leroy A, Wieruszeski JM, Lippens G and Landrieu I. Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein. Proteins, 2012; 80: 454–462.