Impact of Phosphorylation and Pseudophosphorylation on the Early Stages of Aggregation of the Microtubule-Associated Protein Tau

Dmitriy V. Prokopovich, John W. Whittaker, Micaiah M. Muthee, Azka Ahmed, Luca Larini

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The microtubule-associated protein tau regulates the stability of microtubules within neurons in the central nervous system. In turn, microtubules are responsible for the remodeling of the cytoskeleton that ultimately leads to the formation or pruning of new connections among neurons. As a consequence, dysfunction of tau is associated with many forms of dementia as well as Alzheimer's disease. In the brain, tau activity is regulated by its phosphorylation state. Phosphorylation is a post-translational modification of proteins that adds a phosphate group to the side chain of an amino acid. Phosphorylation at key locations in the tau sequence leads to a higher or lower affinity for microtubules. In Alzheimer's disease, tau is present in an abnormal phosphorylation state. However, studying the effect of phosphorylation experimentally has been extremely challenging as there is no viable way of exactly selecting the location and the number of phosphorylated sites. For this reason, researchers have turned to pseudophosphorylation. In this technique, actual phosphorylation is mimicked by mutating the selected amino acid into glutamate or aspartate. Whether this methodology is equivalent to actual phosphorylation is still open to debate. In this study, we will show that phosphorylation and pseudophosphorylation are not exactly equivalent. Although for larger aggregates the two techniques lead to similar structures, the kinetics of the process may be altered. In addition, very little is known about the impact that this may have on the early stages of aggregation, such as nucleation and conformational rearrangement. In this study, we show that the two methods may produce a similar ensemble of conformations, even though the kinetic and chemical details that lead to it are quite different. (Figure Presented).

Original languageEnglish (US)
Pages (from-to)2095-2103
Number of pages9
JournalJournal of Physical Chemistry B
Volume121
Issue number9
DOIs
StatePublished - Mar 9 2017

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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