Structural insight into the conformation of one of the microtubule binding motifs on the Alzheimer’s disease-associated protein tau

O. Cehlar¹, R. Skrabana^1,2, M. NOVAK^1,2

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

²Axon Neuroscience SE, Grosslingova 45, 811 09 Bratislava, Slovakia

The Alzheimer’s disease-associated protein tau is a typical representative of intrinsically disordered proteins (IDPs), existing as a conformational ensemble. Under physiological conditions, tau associates with microtubules and regulates their dynamics, whereas during the progression of neurodegeneration tau dissociates from microtubules, misfolds and creates highly insoluble deposits.

To obtain an insight into the atomic structure of tau, specific monoclonal antibodies can be used as surrogate tau protein binding partners to form complex crystals amenable to X-ray analysis [1]. Here we present the study with the monoclonal antibody Tau5, which has its epitope in the proline rich region of tau [2]. The Fab fragment of Tau5 has been crystallized alone and in complex with 30 amino acid long tau peptide Gly(201)-Arg(230) [3] and the structures were solved to the 1.69 Å resolution. 13 residues from the tau peptide can be modeled in the complex structure, but only some of them make contact with the antibody combining site. The structure of tau polypeptide reveals several important features for which only propensities were previously observed by NMR [4].

This work was supported by the Slovak Research and Development Agency under the contract No. LPP-0038-09 and by the Slovak Grant Agency VEGA grant No. 2/0163/13.

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2. Porzig R, Singer D & Hoffmann R (2007) Epitope mapping of mAbs AT8 and Tau5 directed against hyperphosphorylated regions of the human tau protein. Biochem Biophys Res Commun 358, 644-649,

3. Cehlar O, Skrabana R, Kovac A, Kovacech B & Novak M (2012) Crystallization and preliminary X-ray diffraction analysis of tau protein microtubule-binding motifs in complex with Tau5 and DC25 antibody Fab fragments. Acta Crystallogr F 68, 1181-1185

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