Complementary structural investigation of intrinsically disordered protein tau, involved in neurodegenerative diseases
O. Cehlar1, R. Skrabana1,2, Z. Flachbartova1, M. Novak1,2
aInstitute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 845 10 Bratislava, Slovakia
bAxon Neuroscience GmbH, Rennweg 95/b, A-1030 Vienna, Austria
Microtubule-associated intrinsically disordered protein tau has under physiological conditions very flexible molecule, similar to the random coil [1]. When interacting with microtubules, the proline-rich and repeat regions of tau molecule play the most prominent role [2]. In the course of neurodegenerative tauopathy (e.g. Alzheimer’s disease), tau undergoes numerous posttranslational modifications, dissociates from microtubules and forms highly compact, insoluble paired helical filaments (PHF) [3]. Interestingly, microtubule-interacting sequences on tau constitute the core of the PHF [4].
In our work, the thermodynamics and structure of microtubule binding motifs of tau have been studied with the use of monoclonal antibodies as surrogate tau protein binding partners. Surface plasmon resonance was used to monitor the binding of monoclonal antibody Fab fragment to full length and truncated tau proteins. Thermodynamic analysis showed that specific truncation of tau protein molecule, which was observed under disease conditions [5, 6], results in substantial alteration of tau binding to antibody, pointing to higher accessibility of microtubule binding sequences in truncated tau proteins. To make an insight into structure of tau complexes, Fab fragments have been crystallized alone and with tau peptides. We report preliminary X-ray diffraction analysis of three crystal types diffracting up to 1.72 Å.
Acknowledgement. This work was supported by the Slovak Research and Development Agency under the contracts Nos. LPP-0038-09 and by the Slovak Grant Agency VEGA grants Nos. 2/0162/10, 2/0217/10.