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  

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Control Number  

joongbu:640954