Phosphorylation Impact on the Behavior of Substrate‐Bound Tau

Tau proteins are commonly found in neural cells and provide a variety of functions, the most notable being the regulation of microtubule stability and spacing. Tau aggregation has been implicated in several neurodegenerative diseases, namely dementia and Alzheimer's, making tau‐based therapeutics an area of high research interest. Site‐specific phosphorylation of tau has been observed to direct its behavior but can also result in a lower binding affinity of tau to microtubules, increased propensity of tau to aggregate, and cell death. As the dynamics of tau aggregation are poorly understood, more investigation is needed to elucidate tau aggregation and the effects of phosphorylation. Most of the research in this area has been centered on tau's unbound state, requiring more information regarding the dynamics of its oligomerization upon microtubule binding and cause of disassociation leading to aggregation. To study tau‐tau and tau‐microtubule interactions, we utilized a pseudohyperphosphorylated tau containing seven pseudophosphorylation changes and mimicked the surface of negatively‐charged microtubules with mica. Atomic force microscopy was used to study tau bound to mica, quantify tau‐tau intermolecular interactions, and to assess its bound structure. Changes to solution conditions, such as ionic strength or presence of aggregation inducers, were employed to alter tau's structure and its ability to oligomerize. Comparisons of resulting intermolecular interactions and bound‐tau structures between wild‐type tau and pseudohyperphosphorylated mutants are described, in an effort to address the mechanism linking phosphorylation and tau malfunction. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .