Cabrales Fontela, Yunior

Tau protein is classically considered as a neuronal microtubule-associated protein that stabilizes microtubules and supports the outgrowth of axons. The protein can modulate the transport of vesicles and organelles along microtubules, serves as an anchor for enzymes, and regulates the dynamics of microtubules. Tau is an intrinsically disordered protein, which becomes excessively phosphorylated in Alzheimer’s disease, loses its ability to bind to microtubules and forms neurofibrillary tangles.
Similar to microtubules, actin is another important cytoskeletal protein, which is involved in generation and maintenance of cell morphology and polarity, cell division, contractility, motility, and intracellular trafficking. Microtubule-associated proteins not only regulate microtubule dynamics but bundle actin filaments and cross-link actin filaments with microtubules. In addition, aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer’s disease. Furthermore Hirano bodies, which are actin-rich inclusions, are found in brain histopathological samples of Alzheimer’s disease and related tauopathies.
Although the interaction between Tau and actin has been studied, the nature of the interaction and molecular mechanism involved are still unclear. The intrinsically disordered nature of Tau in solution as well as the dynamic nature of Tau-actin interaction, where even in the bound state part of Tau remains flexible, limits the use of X-ray crystallography to investigate the structure of Tau bound to actin. Therefore we decided to use Nuclear Magnetic Resonance spectroscopy well as other biochemical and biophysical methods to understand the nature of interaction between Tau and actin.
Here we provide insight into the nature of interaction between actin filaments and Tau proteins and the actin-microtubule crosstalk. We show that Tau uses several short helical segments to bind in a dynamic, multivalent process to the hydrophobic pocket of actin. Although a single Tau helix is sufficient to bind to filamentous actin, at least two, flexibly linked α-helices are required for actin bundling. In agreement with a structural model of Tau repeat sequences in complex with actin filaments, phosphorylation at serine 262 attenuates the binding of Tau to filamentous actin. Taken together the data demonstrate that bundling of filamentous actin and cross-linking of the cellular cytoskeleton depends on the metamorphic and multivalent nature of microtubule-associated proteins

Georg-August-University Göttingen

Molecular insights into the Tau-actin interaction

Cabrales-Fontela, Y.

MPG.PuRe