The conformation of proline rich segment of neuronal protein tau studied by the X-ray crystallography, molecular dynamics simulations and biophysical methods

Ondrej Cehlár1,2, Rostislav Škrabana1,2, Mária Janubová2, Radovan Dvorský3, Michal Novák1,2

1Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 845 10 Bratislava, Slovakia

2Axon Neuroscience SE, Dvorakovo Nabrezie 10, 811 02 Bratislava, Slovakia

3Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University, Düsseldorf, Germany

Tau is an intrinsically disordered protein (IDP) implicated in Alzheimer’s disease. Under physiological conditions, tau associates with microtubules and regulates their dynamics, whereas during the progression of neurodegeneration tau dissociates from microtubules, misfolds and creates deposits in the brain tissue. To unravel the conformational properties of microtubule binding tau sequence located in its proline rich region 214Ser-231Thr the monoclonal antibody Tau5 with epitope in this region was used as a tau protein surrogate binding partner [1]. We have determined the conformation of 16 amino acid tau peptide bound in antibody combining site. The stability of this X-ray observed conformation was probed by molecular dynamics simulation. The simulation results were compared with the results obtained for a peptide with mutation T220A that has shown decreased affinity for Tau5 antibody in biophysical measurements.

To this end we have performed unrestrained MD simulations with 9 amino acid long tau peptide 218PPTREPKKV226 that contains all residues that are in contact with antibody paratope in the X-ray structure of the complex, for both wild type and mutated peptide.

Acknowledgement: This work was supported by the Slovak Research and Development Agency under the contract No. LPP-0038-09 and by VEGA grant 2/0177/15.


 [1]       Cehlar O, Skrabana R, Kovac A et al. Crystallization and preliminary X-ray diffraction analysis of tau protein microtubule-binding motifs in complex with Tau5 and DC25 antibody Fab fragments. Acta Crystallographica Section F-Structural Biology and Crystallization Communications 2012; 68: 1181-1185.