Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 45 for “"degron"”.
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Investigating the regulation of plant immunity by the N-degron pathway
… development of disease-resistant crops. The N-degron pathway is a subset of the UPS that relates the stability of a protein to the identity of its N-terminal amino acid residue. Previous work has revealed distinct roles for the N-degron pathway as a regulator of plant defence responses (De …
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Systematic C-degron activity profiling implicates conditional regulation of the CTLH E3 ligase complex in ribosome maturation.
Many E3 ubiquitin ligases recognise specific degron motifs located at protein termini, yet the physiological relevance of these N-degron and C-degron pathways remains poorly understood due to the limited number of validated substrates. Thus, the major aim of this thesis was to define how C-terminal …
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Substrate recognition by the 26S proteasome
… It is known that specific signals (called degrons) on the substrates are recognised by the proteasome, including ubiquitin and a disordered region. The main focus of this thesis is to better understand how the ubiquitin containing degron binds to intrinsic ubiquitin receptors in the 26S …
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Noncanonical recognition and degradation of a stable soluble protein by AAA protease FtsH
… vitro with a sufficiently long degradation tag (degron) and then explore noncanonical recognition as one mechanism that may be employed in FtsH-dependent degradation. In Chapter I, I review our current understanding of AAA+ protease structure and function, especially as it pertains to FtsH to …
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Mechanistic studies of a AAA+ protease
… unfolding, I investigate the degradation of degron-tagged Green Fluorescent Protein (GFP; Chapter 2). By engineering GFP substrates, I determine the steps of GFP unfolding and how structure local to the degron can hinder ClpX-mediated unfolding. In later chapters, my collaborators and I use …
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Harnessing the Anaphase-Promoting Complex for Targeted Protein Degradation
… copies of short linear motifs (SLiMs), termed degrons, that serve as APC/C-recognition sequences. My research approach involved systematically dissecting various combinations of degrons from natural APC/C substrates, primarily using cell-based degradation assays conducted by timelapse …
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Molecular Dissection of the Ubiquitin-Independent Degradation Signal At the Unstructured Amino Terminal End of Human Thymidylate Synthase
… formed by the next 15 residues, functions as a degron, i.e., it is capable of destabilizing a structurally unrelated protein to which it is N-terminally fused. However, the specific amino acids or chemical characteristics of the N-terminus required for its degron activity have not been …
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Mechanism of active substrate delivery by the AAA+ protease adaptor CIpS
… rule substrates. CIpS binds the substrate's N-degron and assembles into a high-affinity CIpS-substrate-CIpA complex, but how the N-degron is transferred from CIpS to the axial pore of the AAA+ CIpA unfoldase to initiate degradation is not known. Here, we demonstrate that the unstructured …
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Conditional Protein Alleles and Regulation of Bacterial Transcription: A Thesis in Two Acts
… with a destabilizing N-terminal sequence (degron) that leads to its degradation. The degron is removed through heterodimerization induced ubiquitin complementation and cleavage. This stabilizes the protein and allows a build up of activity. These techniques should allow the manipulation of …
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The role of the N domain in substrate binding, oligomerization, and allosteric regulation of the AAA+ Lon protease
… targeted to AAA+ proteases by degradation tags (degrons). In E. coli, the Lon protease is responsible for the degradation of numerous regulatory proteins, including the cell-division inhibitor SulA, but also recognizes and degrades the majority of misfolded proteins. How Lon recognizes and …
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Identification of EWS-FLI1 Regions Necessary for Ewing Sarcoma Proliferation
… report shows the adaptation of two inducible degron systems, Small Molecule Assisted Shut-Off (SMASh) and Auxin-inducible degron (AID), into the endogenous locus of EF in a series of Ewing sarcoma cell lines to define the phenotype of EF depletion. Across multiple cell line and degradation …
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Dissecting the function of MYEF2 in neural stem cells and glioblastoma
… thesis, I also describe the use of SMASh tag degron technology to precisely control the degradation of SOX2 in mouse NSCs. SMASh, a drug degradable selfcleaving degron, was fused to the C-terminal of endogenous SOX2 in mouse NSCs. We find that this works well and can therefore be a powerful …
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The Non-Wnt Functions of APC: Unravelling the Link between APC and Apoptosis
… non-Wnt functions of APC. To this end, I created degron-tagged APC in DT40 cells that allowed for the rapid, conditional degradation of endogenous APC. The aim was to identify the immediate effects on cellular processes. Then, to identify the contribution of different APC domains by measuring the …
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Structural Principles of Substrate Recognition and Unfolding by the ClpAP and ClpXP AAA+ Proteases
… peptide sequences in the substrate (called degrons), substrate-tethering sequences (called enhancement- or e-tags), and adaptor proteins. My thesis examines the structural basis of substrate recognition and degradation by the bacterial AAA+ proteases ClpAP and ClpXP, which are composed of …
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Regulation of BubR1 by Ultraviolet Radiation: Implications in Skin Cancer
… binding specific substrates through a conserved degron motif and targeting them for ubiquitination and subsequent proteasome degradation. BubR1 contains a putative β-TRCP degron motif, indicating the possibility that β-TRCP may play a role in regulating BubR1 stability under various stimuli. …
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The Functional Role for Chromatin Loops in Gene Expression Control During Human Neuron Maturation
… model systems, and build an auxin-inducible degron to deplete the architectural protein CTCF and disrupt loops genome-wide on short time scales during human induced pluripotent stem cell (iPSC)-derived post-mitotic neuronal maturation. We find thousands of ablated and hundreds of ectopically …
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High-throughput functionalization of the Toxoplasma kinome uncovers a novel regulator of invasion and egress
… label protein kinases with an auxin-inducible degron and fluorophore. Hundreds of tagging vectors were assembled from synthetic sequences in a single reaction and used to generate pools of mutants to determine localization and function. Examining 1,160 arrayed clones, I assigned 40 protein …
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Molecular mediators of cardiac-specific enhancer activation
… commitment. We then used an inducible degron-tag strategy to conditionally deplete TEAD1 and observed an abnormal beating phenotype in CMs. Further mechanistic studies revealed that TEAD1 was necessary for the activity of a subset of cardiac enhancers putatively linked to cell-cell …
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Inquiries into the Mycobacterial Caseinolytic Protease System
… by ClpC1 through recognition of an N-terminal degron sequence. Such hits contribute to the short list of documented mycobacterial Clp substrates and directly implicate the ClpC1 chaperone in transcriptional regulation. Fluorescent degradation assays successfully identified novel C-terminal …
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The Cell-Essentiality of KAT7 in Acute Myeloid Leukemia
… leukemic programme. Using the auxin-inducible degron (AID) system to induce rapid KAT7 protein degradation, I showed that KAT7 is required for the recruitment of the MLL-fusion associated adaptor proteins such as BRD4 and AF4 to gene promoters, which are critical for the maintenance of the …
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