東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Role of a Highly Conserved Region of...

Shaffer, Robert Abraham.

FindBook

Google Book

Amazon

博客來

Role of a Highly Conserved Region of the NF-kappaB Essential Modulator in Its Scaffolding Function.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Role of a Highly Conserved Region of the NF-kappaB Essential Modulator in Its Scaffolding Function./
作者:	Shaffer, Robert Abraham.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	232 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
標題:	Molecular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10844798
ISBN:	9780438886674

Role of a Highly Conserved Region of the NF-kappaB Essential Modulator in Its Scaffolding Function.
Shaffer, Robert Abraham.

Role of a Highly Conserved Region of the NF-kappaB Essential Modulator in Its Scaffolding Function. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 232 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--Boston University, 2018.

This item must not be sold to any third party vendors.

Scaffold proteins facilitate many aspects of intracellular signaling. These proteins can regulate two or more proteins in the same pathway, or coordinate signaling from multiple pathways. Scaffold proteins are therefore key control points for the flux of signaling and play essential roles in biological systems. There are four possible mechanisms by which scaffold proteins achieve activation and propagate signaling: 1) rigid protein binding between two or more proteins to co-localize binding partners, 2) ligand-induced activation such as may result from a conformational change, 3) disorder-to-order transition where the scaffold protein folds as a result of a protein-protein interaction, and 4) dynamic processes such as phosphorylation. The scaffold protein NF-κB essential modulator (NEMO) functions via ligand-induced activation and serves as the key control point for canonical NF-κB signaling. The work described in this thesis investigates the role of a previously uncharacterized domain within NEMO that is required for function, which we term the Intervening Domain (IVD). Bioinformatic analysis reveals a high level of sequence conservation across species within this domain. Conformational changes following ligand binding are observed for NEMO and these changes require conserved sequences in the IVD. Additionally, a functional IVD is shown to increase the binding affinity of NEMO for IKKβ, enhance the thermal stability of NEMO, and is required to propagate NF-κB signaling in cells. A fluorescence-based assay is also developed to characterize the formation of a complex composed of NEMO, a zinc ion, and IκBα. A separate fluorescence-based assay is developed to measure IKK activity and is used to determine that NEMO alone or in the presence of linear tetraubiquitin does not enhance the rate of IKKβ phosphorylation of an IκBα-derived peptide. Furthermore, a number of organic small molecules and macrocycles are screened against the NEMO-IKKβ interaction. One small molecule was validated as an inhibitor and its biophysical properties and inhibition kinetics are described in this thesis. These analyses represent the first characterization of a highly conserved domain required for the function of the key control point in NF-κB signaling. The IVD domain of NEMO could be targeted for development of an allosteric effector for therapeutic discovery.

ISBN: 9780438886674Subjects--Topical Terms:

517296
Molecular biology.

Role of a Highly Conserved Region of the NF-kappaB Essential Modulator in Its Scaffolding Function.
LDR:03505nmm a2200337 4500 001 2210485
005 20191121124228.5
008 201008s2018 ||||||||||||||||| ||eng d
020 $a 9780438886674
035 $a (MiAaPQ)AAI10844798
035 $a (MiAaPQ)bu:14063
035 $a AAI10844798
040 $a MiAaPQ $c MiAaPQ
100 1 $a Shaffer, Robert Abraham. $3 3437625
245 1 0 $a Role of a Highly Conserved Region of the NF-kappaB Essential Modulator in Its Scaffolding Function.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2018
300 $a 232 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Whitty, Adrian;Allen, Karen N.
502 $a Thesis (Ph.D.)--Boston University, 2018.
506 $a This item must not be sold to any third party vendors.
520 $a Scaffold proteins facilitate many aspects of intracellular signaling. These proteins can regulate two or more proteins in the same pathway, or coordinate signaling from multiple pathways. Scaffold proteins are therefore key control points for the flux of signaling and play essential roles in biological systems. There are four possible mechanisms by which scaffold proteins achieve activation and propagate signaling: 1) rigid protein binding between two or more proteins to co-localize binding partners, 2) ligand-induced activation such as may result from a conformational change, 3) disorder-to-order transition where the scaffold protein folds as a result of a protein-protein interaction, and 4) dynamic processes such as phosphorylation. The scaffold protein NF-κB essential modulator (NEMO) functions via ligand-induced activation and serves as the key control point for canonical NF-κB signaling. The work described in this thesis investigates the role of a previously uncharacterized domain within NEMO that is required for function, which we term the Intervening Domain (IVD). Bioinformatic analysis reveals a high level of sequence conservation across species within this domain. Conformational changes following ligand binding are observed for NEMO and these changes require conserved sequences in the IVD. Additionally, a functional IVD is shown to increase the binding affinity of NEMO for IKKβ, enhance the thermal stability of NEMO, and is required to propagate NF-κB signaling in cells. A fluorescence-based assay is also developed to characterize the formation of a complex composed of NEMO, a zinc ion, and IκBα. A separate fluorescence-based assay is developed to measure IKK activity and is used to determine that NEMO alone or in the presence of linear tetraubiquitin does not enhance the rate of IKKβ phosphorylation of an IκBα-derived peptide. Furthermore, a number of organic small molecules and macrocycles are screened against the NEMO-IKKβ interaction. One small molecule was validated as an inhibitor and its biophysical properties and inhibition kinetics are described in this thesis. These analyses represent the first characterization of a highly conserved domain required for the function of the key control point in NF-κB signaling. The IVD domain of NEMO could be targeted for development of an allosteric effector for therapeutic discovery.
590 $a School code: 0017.
650 4 $a Molecular biology. $3 517296
650 4 $a Biochemistry. $3 518028
650 4 $a Biophysics. $3 518360
690 $a 0307
690 $a 0487
690 $a 0786
710 2 $a Boston University. $b Molecular Biology, Cell Biology & Biochemistry. $3 3437626
773 0 $t Dissertations Abstracts International $g 80-09B.
790 $a 0017
791 $a Ph.D.
792 $a 2018
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10844798