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Insights on the Functional Importance of Molecular Motions in Phosphatases
Insights on the Functional Importance of Molecular Motions in Phosphatases
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211150948
- ISBN
- 9798383566558
- DDC
- 574
- 서명/저자
- Insights on the Functional Importance of Molecular Motions in Phosphatases
- 발행사항
- [Sl] : Yale University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 405 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
- 주기사항
- Advisor: Loria, Joseph P.
- 학위논문주기
- Thesis (Ph.D.)--Yale University, 2024.
- 초록/해제
- 요약Enzymes are biomolecules that catalyze biological reactions, and as such, demand thorough investigation so that manipulation of their associated biological processes can be achieved. Biological processes are made up of complex pathways where enzymes play a key role in regulating pathway flux. Enzymes are a diverse subset of biomolecules and different classes of enzymes regulate pathway activity in different ways. For example, phosphatases and kinases are the enzymes responsible for regulating the phosphorylation levels of proteins. Phosphatases remove phosphates by catalyzing the hydrolysis of phosphate groups and kinases attach phosphate groups by catalyzing the transfer of phosphates from adenosine triphosphate (ATP) to their target protein. Protein phosphorylation is an important type of post-translational modification that alters the functionality of a protein and has profound effects on cellular signaling networks. The phosphorylation state of an enzyme can enhance or inhibit the catalytic rate of as well as enable or hinder the enzyme's ability to interact with other proteins. Because protein phosphorylation influences protein and cellular function, it is imperative to pursue a strong understanding of the enzymes that regulate it. The work I present here will focus solely on two types of phosphatases, protein tyrosine phosphatases (PTPs) and protein histidine phosphatases (PHPs).Phosphatases themselves are subject to regulation and the many ways in which this occurs is the core of this thesis. Ultimately, the catalytic activity of a phosphatase is a result of how favorably it can interact with its substrates and how fast it can catalyze its reaction. However, it is the interactions occurring intramolecularly that regulate the enzyme-substrate interaction. This is because the ability of a phosphatase to perform its function is fundamentally defined by its structural conformation at a given point in time and changes to its conformation over time. For a phosphatase to be catalytically active, its active site must be structured in a manner that allows for the chemistry needed to occur to be physically possible. These catalytically active conformations can be thought of as 'on' states, whereas conformations that are not catalytically active can be thought of as 'off' states. Phosphatases, like many proteins, can sample a wide range of conformations because they are dynamic molecules with different parts constantly moving and interacting with each other. The interacting parts often form a residue network where the motion of one residue influences the motions of another despite being spatially distant, a phenomenon known as allostery. Undoubtedly, the active site should be investigated when establishing the structure-function relationship of an enzyme, but so should allosteric sites and the network of residues bridging the two sites. A varying number of residues can make up a protein and as the size of the protein increases, so too does the complexity of the intramolecular interactions. We can simplify this by categorizing the conformations as either 'on' or 'off' and framing questions with this mindset. Despite this two-state approach, the diversity of proteins often gives rise to unique and discrete interactions governing their function. Identifying these interactions provides a path for the development of targeted drug therapeutics and so a technique that can inform on these interactions is needed. NMR spectroscopy is especially suited for characterizing dynamic structural features and will be heavily featured in this thesis. NMR spectroscopy can provide atomistic information on the entire protein structure as well as inform on the dynamics of those structures. Using NMR, I have studied four different phosphatase systems, mPTPA, VHR, SsoPTP, and PHPT1. In this thesis I present mechanistic insights to better understand their function.
- 일반주제명
- Biochemistry
- 일반주제명
- Biophysics
- 일반주제명
- Chemistry
- 키워드
- Allostery
- 키워드
- Protein Dynamics
- 키워드
- Solution NMR
- 기타저자
- Yale University Molecular Biophysics and Biochemistry
- 기본자료저록
- Dissertations Abstracts International. 86-01B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211150948
■006m o d
■007cr#unu||||||||
■020 ▼a9798383566558
■035 ▼a(MiAaPQ)AAI30992688
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aZavala, Erik Xavier.
■24510▼aInsights on the Functional Importance of Molecular Motions in Phosphatases
■260 ▼a[Sl]▼bYale University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a405 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-01, Section: B.
■500 ▼aAdvisor: Loria, Joseph P.
■5021 ▼aThesis (Ph.D.)--Yale University, 2024.
■520 ▼aEnzymes are biomolecules that catalyze biological reactions, and as such, demand thorough investigation so that manipulation of their associated biological processes can be achieved. Biological processes are made up of complex pathways where enzymes play a key role in regulating pathway flux. Enzymes are a diverse subset of biomolecules and different classes of enzymes regulate pathway activity in different ways. For example, phosphatases and kinases are the enzymes responsible for regulating the phosphorylation levels of proteins. Phosphatases remove phosphates by catalyzing the hydrolysis of phosphate groups and kinases attach phosphate groups by catalyzing the transfer of phosphates from adenosine triphosphate (ATP) to their target protein. Protein phosphorylation is an important type of post-translational modification that alters the functionality of a protein and has profound effects on cellular signaling networks. The phosphorylation state of an enzyme can enhance or inhibit the catalytic rate of as well as enable or hinder the enzyme's ability to interact with other proteins. Because protein phosphorylation influences protein and cellular function, it is imperative to pursue a strong understanding of the enzymes that regulate it. The work I present here will focus solely on two types of phosphatases, protein tyrosine phosphatases (PTPs) and protein histidine phosphatases (PHPs).Phosphatases themselves are subject to regulation and the many ways in which this occurs is the core of this thesis. Ultimately, the catalytic activity of a phosphatase is a result of how favorably it can interact with its substrates and how fast it can catalyze its reaction. However, it is the interactions occurring intramolecularly that regulate the enzyme-substrate interaction. This is because the ability of a phosphatase to perform its function is fundamentally defined by its structural conformation at a given point in time and changes to its conformation over time. For a phosphatase to be catalytically active, its active site must be structured in a manner that allows for the chemistry needed to occur to be physically possible. These catalytically active conformations can be thought of as 'on' states, whereas conformations that are not catalytically active can be thought of as 'off' states. Phosphatases, like many proteins, can sample a wide range of conformations because they are dynamic molecules with different parts constantly moving and interacting with each other. The interacting parts often form a residue network where the motion of one residue influences the motions of another despite being spatially distant, a phenomenon known as allostery. Undoubtedly, the active site should be investigated when establishing the structure-function relationship of an enzyme, but so should allosteric sites and the network of residues bridging the two sites. A varying number of residues can make up a protein and as the size of the protein increases, so too does the complexity of the intramolecular interactions. We can simplify this by categorizing the conformations as either 'on' or 'off' and framing questions with this mindset. Despite this two-state approach, the diversity of proteins often gives rise to unique and discrete interactions governing their function. Identifying these interactions provides a path for the development of targeted drug therapeutics and so a technique that can inform on these interactions is needed. NMR spectroscopy is especially suited for characterizing dynamic structural features and will be heavily featured in this thesis. NMR spectroscopy can provide atomistic information on the entire protein structure as well as inform on the dynamics of those structures. Using NMR, I have studied four different phosphatase systems, mPTPA, VHR, SsoPTP, and PHPT1. In this thesis I present mechanistic insights to better understand their function.
■590 ▼aSchool code: 0265.
■650 4▼aBiochemistry
■650 4▼aBiophysics
■650 4▼aChemistry
■653 ▼aAllostery
■653 ▼aMolecular Motions
■653 ▼aProtein Dynamics
■653 ▼aProtein Histidine Phosphatases
■653 ▼aProtein Tyrosine Phosphatases
■653 ▼aSolution NMR
■690 ▼a0487
■690 ▼a0786
■690 ▼a0485
■71020▼aYale University▼bMolecular Biophysics and Biochemistry.
■7730 ▼tDissertations Abstracts International▼g86-01B.
■790 ▼a0265
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17160275▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
