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Structural Insights Into the Role of the Proline Rich Region in Tau Function With Tubulin and Microtubules
Structural Insights Into the Role of the Proline Rich Region in Tau Function With Tubulin and Microtubules
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151347
- ISBN
- 9798382830292
- DDC
- 574
- 저자명
- Acosta, Karen.
- 서명/저자
- Structural Insights Into the Role of the Proline Rich Region in Tau Function With Tubulin and Microtubules
- 발행사항
- [Sl] : University of Pennsylvania, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 124 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- 주기사항
- Advisor: Rhoades, Elizabeth.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2024.
- 초록/해제
- 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.
- 일반주제명
- Biochemistry
- 일반주제명
- Biophysics
- 일반주제명
- Molecular physics
- 일반주제명
- Neurosciences
- 일반주제명
- Analytical chemistry
- 키워드
- Microtubules
- 키워드
- Phosphorylation
- 키워드
- Tau
- 키워드
- Tubulin
- 기타저자
- University of Pennsylvania Biochemistry and Molecular Biophysics
- 기본자료저록
- Dissertations Abstracts International. 85-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151347
■006m o d
■007cr#unu||||||||
■020 ▼a9798382830292
■035 ▼a(MiAaPQ)AAI31242744
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aAcosta, Karen.
■24510▼aStructural Insights Into the Role of the Proline Rich Region in Tau Function With Tubulin and Microtubules
■260 ▼a[Sl]▼bUniversity of Pennsylvania▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a124 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-12, Section: B.
■500 ▼aAdvisor: Rhoades, Elizabeth.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2024.
■520 ▼aTau 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.
■590 ▼aSchool code: 0175.
■650 4▼aBiochemistry
■650 4▼aBiophysics
■650 4▼aMolecular physics
■650 4▼aNeurosciences
■650 4▼aAnalytical chemistry
■653 ▼aIntrinsically disordered protein
■653 ▼aMicrotubules
■653 ▼aPhosphorylation
■653 ▼aPost-translational modification
■653 ▼aTau
■653 ▼aTubulin
■690 ▼a0487
■690 ▼a0786
■690 ▼a0609
■690 ▼a0486
■690 ▼a0317
■71020▼aUniversity of Pennsylvania▼bBiochemistry and Molecular Biophysics.
■7730 ▼tDissertations Abstracts International▼g85-12B.
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17161371▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
