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Mechanistic Dissection of Substrate Recruitment by Ubiquitin Ligases- [electronic resource]
Mechanistic Dissection of Substrate Recruitment by Ubiquitin Ligases- [electronic resource]
상세정보
- 자료유형
- 학위논문
- Control Number
- 0016934825
- International Standard Book Number
- 9798380848787
- Dewey Decimal Classification Number
- 574
- Main Entry-Personal Name
- Ma, Michelle W.
- Publication, Distribution, etc. (Imprint
- [S.l.] : Harvard University., 2023
- Publication, Distribution, etc. (Imprint
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Physical Description
- 1 online resource(231 p.)
- General Note
- Source: Dissertations Abstracts International, Volume: 85-05, Section: B.
- General Note
- Advisor: Fischer, Eric.
- Dissertation Note
- Thesis (Ph.D.)--Harvard University, 2023.
- Restrictions on Access Note
- This item must not be sold to any third party vendors.
- Summary, Etc.
- 요약Protein homeostasis is an essential process that needs to be tightly regulated to maintain a delicate balance between protein synthesis and protein degradation. The Ubiquitin Proteasome System (UPS) serves as a fundamental regulatory pathway for controlling protein degradation, of which E3 ligases lend additional specificity in targeting and degrading their substrates. Investigating the variety of mechanisms that ubiquitin ligases rely on allows us to understand how diverse substrates are recruited. Targeted protein degradation (TPD) is an emerging field that utilizes small molecules - either PROTACs or small molecules - to hijack E3 ligases and direct them to neo-substrates for ubiquitylation and subsequent degradation. However, the discovery of new degraders is hindered by the lack of understanding underlying these degraders' mechanism of action and how they co-opt existing mechanisms in nature. My thesis work includes three projects that leverages a combination of biochemistry, structural biology, chemical biology, and proteomics to dissect the mechanistic details of how ubiquitin ligases interact with their substrates both in endogenous and drug-induced settings. In Chapter 2, I combined biochemistry and structural biology to interrogate DCAF16-based molecular glue degraders and discovered a novel "template-assisted covalent modification" mechanism. In Chapter 3, I contributed to structure-function studies for HUWE1 and characterized various classes of HUWE1 mutants with biochemical assays. In Chapter 4, I developed a novel mass spectrometry-based tool to provide temporal resolution for cellular perturbations, specifically looking at the intertwined network of E3 ligases and DUBs. These findings enhance our existing comprehension of the mechanisms of ubiquitin ligases, potentially advancing the exploration and advancement of degraders.
- Subject Added Entry-Topical Term
- Biochemistry.
- Subject Added Entry-Topical Term
- Cellular biology.
- Subject Added Entry-Topical Term
- Molecular biology.
- Index Term-Uncontrolled
- Targeted protein degradation
- Index Term-Uncontrolled
- Ubiquitin ligases
- Index Term-Uncontrolled
- Protein homeostasis
- Index Term-Uncontrolled
- Structural biology
- Index Term-Uncontrolled
- Protein degradation
- Added Entry-Corporate Name
- Harvard University Biology Molecular and Cellular
- Host Item Entry
- Dissertations Abstracts International. 85-05B.
- Host Item Entry
- Dissertation Abstract International
- Electronic Location and Access
- 로그인을 한후 보실 수 있는 자료입니다.
- Control Number
- joongbu:640954
MARC
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■020 ▼a9798380848787
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aMa, Michelle W.▼0(orcid)0000-0002-7834-2129
■24510▼aMechanistic Dissection of Substrate Recruitment by Ubiquitin Ligases▼h[electronic resource]
■260 ▼a[S.l.]▼bHarvard University. ▼c2023
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2023
■300 ▼a1 online resource(231 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-05, Section: B.
■500 ▼aAdvisor: Fischer, Eric.
■5021 ▼aThesis (Ph.D.)--Harvard University, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aProtein homeostasis is an essential process that needs to be tightly regulated to maintain a delicate balance between protein synthesis and protein degradation. The Ubiquitin Proteasome System (UPS) serves as a fundamental regulatory pathway for controlling protein degradation, of which E3 ligases lend additional specificity in targeting and degrading their substrates. Investigating the variety of mechanisms that ubiquitin ligases rely on allows us to understand how diverse substrates are recruited. Targeted protein degradation (TPD) is an emerging field that utilizes small molecules - either PROTACs or small molecules - to hijack E3 ligases and direct them to neo-substrates for ubiquitylation and subsequent degradation. However, the discovery of new degraders is hindered by the lack of understanding underlying these degraders' mechanism of action and how they co-opt existing mechanisms in nature. My thesis work includes three projects that leverages a combination of biochemistry, structural biology, chemical biology, and proteomics to dissect the mechanistic details of how ubiquitin ligases interact with their substrates both in endogenous and drug-induced settings. In Chapter 2, I combined biochemistry and structural biology to interrogate DCAF16-based molecular glue degraders and discovered a novel "template-assisted covalent modification" mechanism. In Chapter 3, I contributed to structure-function studies for HUWE1 and characterized various classes of HUWE1 mutants with biochemical assays. In Chapter 4, I developed a novel mass spectrometry-based tool to provide temporal resolution for cellular perturbations, specifically looking at the intertwined network of E3 ligases and DUBs. These findings enhance our existing comprehension of the mechanisms of ubiquitin ligases, potentially advancing the exploration and advancement of degraders.
■590 ▼aSchool code: 0084.
■650 4▼aBiochemistry.
■650 4▼aCellular biology.
■650 4▼aMolecular biology.
■653 ▼aTargeted protein degradation
■653 ▼aUbiquitin ligases
■653 ▼aProtein homeostasis
■653 ▼aStructural biology
■653 ▼aProtein degradation
■690 ▼a0487
■690 ▼a0379
■690 ▼a0307
■71020▼aHarvard University▼bBiology, Molecular and Cellular.
■7730 ▼tDissertations Abstracts International▼g85-05B.
■773 ▼tDissertation Abstract International
■790 ▼a0084
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16934825▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
