STRUCTURAL INSIGHTS INTO THE ROLE OF THE PROLINE RICH REGION IN TAU FUNCTION WITH TUBULIN AND MICROTUBULES

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Biochemistry and Molecular Biophysics
Discipline
Biochemistry, Biophysics, and Structural Biology
Biochemistry, Biophysics, and Structural Biology
Physics
Subject
intrinsically disordered protein
microtubule
phosphorylation
PTM
tau
tubulin
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Copyright date
01/01/2024
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Author
Acosta, Karen
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Abstract

Tau is a microtubule-associated protein thought to function in the regulation of microtubule stability and dynamics. Normally, tau plays an important role in modulating axonal microtubules in neurons, where it is highly expressed. Intracellular tau aggregates are found in a broad class of disorders, including Alzheimer’s Disease, termed tauopathies. As an intrinsically disordered protein, tau lacks stable secondary and tertiary structure, and this structural disorder is maintained even when binding to soluble tubulin and microtubules. Multiple tau-tubulin binding sites have also been identified, spanning the proline-rich region (PRR), microtubule binding repeats (MTBR: R1–R4), and pseudo-repeat, R′. Although dozens of post-translational modifications have been identified on tau, phosphorylation, and specifically hyperphosphorylation, of tau is correlated with disease and alterations to microtubule binding. Intriguingly, potential phosphorylation sites also cluster with high frequency within the PRR. Here, we use single-molecule spectroscopy and structural mass spectrometry techniques to characterize the impact of phosphomimic mutations in the PRR on tubulin binding and probe the structure of the PRR-tubulin complex. We find that phosphomimics cumulatively diminish tubulin binding and slow microtubule polymerization. Additionally, we map two ~15 residue regions of the PRR as primary tubulin binding sites and propose a model in which PRR enhances lateral interactions between tubulin dimers, complementing the longitudinal interactions observed for MTBR. Together these measurements provide insight into the previously overlooked relevance of tau’s PRR in functional interactions with tubulin.

Advisor
Rhoades, Elizabeth
Date of degree
2024
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