Material Type  

 학위논문

 

0017161371

Date and Time of Latest Transaction  

20250211151347

ISBN  

9798382830292

DDC  

574

Author  

Acosta, Karen.

Title/Author  

Structural Insights Into the Role of the Proline Rich Region in Tau Function With Tubulin and Microtubules.

Publish Info  

[S.l.] : University of Pennsylvania., 2024

Publish Info  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Material Info  

124 p.

General Note  

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

General Note  

Advisor: Rhoades, Elizabeth.

학위논문주기  

Thesis (Ph.D.)--University of Pennsylvania, 2024.

Abstracts/Etc  

요약Tau 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.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Biophysics.

Subject Added Entry-Topical Term  

Molecular physics.

Subject Added Entry-Topical Term  

Neurosciences.

Subject Added Entry-Topical Term  

Analytical chemistry.

Index Term-Uncontrolled  

Intrinsically disordered protein

Index Term-Uncontrolled  

Microtubules

Index Term-Uncontrolled  

Phosphorylation

Index Term-Uncontrolled  

Post-translational modification

Index Term-Uncontrolled  

Tau

Index Term-Uncontrolled  

Tubulin

Added Entry-Corporate Name  

University of Pennsylvania Biochemistry and Molecular Biophysics

Host Item Entry  

Dissertations Abstracts International. 85-12B.

Electronic Location and Access  

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Control Number  

joongbu:658374