The Laboratory of Structural Biology of Neurodegeneration focusses in the first place on describing the physiological and pathophysiological role of intrinsically disordered tau protein in Alzheimer’s disease using the approaches of structural biology and biophysics. The second interest consists in examination of general principles of the conformation behaviour of disordered proteins.
Primary experimental approach represents the crystallization of tau polypeptides in complexes with Fab fragments of monoclonal antibodies created mostly at the Institute of Neuroimmunology by hybridoma technology. Back in 2007, the first structural information about the Alzheimer’s disease tau filaments was revealed following crystallization of the filament core C-terminal hexapeptide in complex with the core-specific monoclonal antibody MN423 [1]. Since then, other complexes of Fab targeting different tau regions were crystallized [2].
The second approach represents the biophysical characterisation of tau monomeric and polymerized forms and their interaction with antibodies and other binding partners. The laboratory has a long history in using surface plasmon resonance (SPR) and serves as an unformal reference lab for this technique. Other available methods for proteins include isothermal titration calorimetry (ITC), differential scanning calorimetry, dynamic light scattering and Fourier transform infrared spectroscopy. Recently we have published an interaction study characterising the binding of C-terminal specific tau antibody to 12 various tau proteins using SPR, microscale thermophoresis and cross-linking mass spectrometry [3].
The third approach represents the characterisation of tau conformations using molecular dynamics simulations and the comparison of conformations obtained with simulations of tau peptides in free state in solution with conformation of respective tau peptide from the complex with antibody Fab fragment.
During last twenty years the lab members participated in more than 15 different projects with several Slovak and European scientific teams, procuring the interaction and structural parameters of various biological complexes. E.g., collaboration with the company Axon Neuroscience R&D Services SE contributed to the development of passive [4] and active Alzheimer’s disease immunotherapy and to the evaluation of affinity maturation of antibodies generated during the phase II clinical trial. The antibody candidates neutralizing SARS CoV 2 were also characterized by SPR [5].
We are committed to continue sharing our expertise. Currently running collaboration projects examine innate immunity player lactoferrin, regulation of plasminogen activation or universal adaptor protein 14-3-3.
This work was supported by the grant number APVV-21-0479.