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Regulation of Tyrosine Phosphatases Through Protein-Protein Interactions
Regulation of Tyrosine Phosphatases Through Protein-Protein Interactions
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152825
- ISBN
- 9798384476788
- DDC
- 540
- 서명/저자
- Regulation of Tyrosine Phosphatases Through Protein-Protein Interactions
- 발행사항
- [Sl] : Columbia University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 109 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-04, Section: B.
- 주기사항
- Advisor: Shah, Neel H.
- 학위논문주기
- Thesis (Ph.D.)--Columbia University, 2024.
- 초록/해제
- 요약The rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter cell signaling or protein function. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized. Alternatively, protein-protein interactions can allosterically regulate function, enhancing or suppressing activity in response to binding. In this work, we investigate the interaction between the tyrosine phosphatase PTP1B and the adaptor protein Grb2, which have been annotated as binding partners in a number of proteomics studies. This interaction has been postulated to colocalize PTP1B with its substrate IRS-1 by forming a ternary complex, thereby enhancing the dephosphorylation of IRS-1 to suppress insulin signaling. Here, we report that Grb2 binding to PTP1B also allosterically enhances PTP1B catalytic activity. We show that this interaction is dependent on the proline-rich region of PTP1B, which interacts with the C-terminal SH3 domain of Grb2. Using NMR spectroscopy and hydrogen-deuterium exchange mass spectrometry (HDXMS) we show that Grb2 binding alters PTP1B structure and/or dynamics. Finally, we use MS proteomics to identify other interactors of the PTP1B proline-rich region that may also regulate PTP1B function similarly to Grb2. This work presents one of the first examples of a protein allosterically regulating the enzymatic activity of PTP1B and lays the foundation for discovering new mechanisms of PTP1B regulation in cell signaling.
- 일반주제명
- Chemistry
- 일반주제명
- Biochemistry
- 일반주제명
- Biophysics
- 일반주제명
- Cellular biology
- 일반주제명
- Analytical chemistry
- 키워드
- Allostery
- 키워드
- Grb2
- 키워드
- PTP1B
- 키워드
- SH3 domain
- 기타저자
- Columbia University Chemistry
- 기본자료저록
- Dissertations Abstracts International. 86-04B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211152825
■006m o d
■007cr#unu||||||||
■020 ▼a9798384476788
■035 ▼a(MiAaPQ)AAI31560026
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a540
■1001 ▼aChartier, Cassandra A.
■24510▼aRegulation of Tyrosine Phosphatases Through Protein-Protein Interactions
■260 ▼a[Sl]▼bColumbia University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a109 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-04, Section: B.
■500 ▼aAdvisor: Shah, Neel H.
■5021 ▼aThesis (Ph.D.)--Columbia University, 2024.
■520 ▼aThe rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter cell signaling or protein function. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized. Alternatively, protein-protein interactions can allosterically regulate function, enhancing or suppressing activity in response to binding. In this work, we investigate the interaction between the tyrosine phosphatase PTP1B and the adaptor protein Grb2, which have been annotated as binding partners in a number of proteomics studies. This interaction has been postulated to colocalize PTP1B with its substrate IRS-1 by forming a ternary complex, thereby enhancing the dephosphorylation of IRS-1 to suppress insulin signaling. Here, we report that Grb2 binding to PTP1B also allosterically enhances PTP1B catalytic activity. We show that this interaction is dependent on the proline-rich region of PTP1B, which interacts with the C-terminal SH3 domain of Grb2. Using NMR spectroscopy and hydrogen-deuterium exchange mass spectrometry (HDXMS) we show that Grb2 binding alters PTP1B structure and/or dynamics. Finally, we use MS proteomics to identify other interactors of the PTP1B proline-rich region that may also regulate PTP1B function similarly to Grb2. This work presents one of the first examples of a protein allosterically regulating the enzymatic activity of PTP1B and lays the foundation for discovering new mechanisms of PTP1B regulation in cell signaling.
■590 ▼aSchool code: 0054.
■650 4▼aChemistry
■650 4▼aBiochemistry
■650 4▼aBiophysics
■650 4▼aCellular biology
■650 4▼aAnalytical chemistry
■653 ▼aAllostery
■653 ▼aGrb2
■653 ▼aProtein tyrosine phosphatase
■653 ▼aProtein-protein interaction
■653 ▼aPTP1B
■653 ▼aSH3 domain
■690 ▼a0485
■690 ▼a0487
■690 ▼a0786
■690 ▼a0379
■690 ▼a0486
■71020▼aColumbia University▼bChemistry.
■7730 ▼tDissertations Abstracts International▼g86-04B.
■790 ▼a0054
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17164048▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
