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

The Molecular and Regulatory Mechani...

Deng, Sunbin.

FindBook

Google Book

Amazon

博客來

The Molecular and Regulatory Mechanism of Multi-Subunit N-Terminal Acetyltransferases.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Molecular and Regulatory Mechanism of Multi-Subunit N-Terminal Acetyltransferases./
作者:	Deng, Sunbin.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	212 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-12, Section: B.
Contained By:	Dissertations Abstracts International82-12B.
標題:	Biochemistry. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28319067
ISBN:	9798738619526

The Molecular and Regulatory Mechanism of Multi-Subunit N-Terminal Acetyltransferases.
Deng, Sunbin.

The Molecular and Regulatory Mechanism of Multi-Subunit N-Terminal Acetyltransferases. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 212 p.

Source: Dissertations Abstracts International, Volume: 82-12, Section: B.

Thesis (Ph.D.)--University of Pennsylvania, 2021.

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

N-terminal acetylation (NTA) is one of the most widespread protein modifications, which occurs on most eukaryotic proteins, but is significantly less common on bacterial and archaea proteins. This modification is carried out by a family of enzymes called N-terminal acetyltransferases (NATs). To date, 12 NATs have been identified, harboring different composition, substrate specificity, and in some cases, modes of regulation. In the first chapter, we review the molecular features of NATs.NatA/E, NatB and NatC, are multi-subunit enzymes, responsible for the majority of eukaryotic protein NTA. Their mechanisms of action and regulation remain poorly understood before this dissertation. In the second chapter, we determined the X-ray crystal structure of yeast NatA/Naa50 as a scaffold to understand coregulation of NatA/Naa50 activity in both yeast and human. We found that Naa50 makes evolutionarily conserved contacts to both the Naa10 and Naa15 subunits of NatA. These interactions promote catalytic crosstalk within the human complex, but do so to a lesser extent in the yeast complex, where Naa50 activity is compromised.Thirdly, we reported the Cryo-EM structures of human NatE and NatE/HYPK complexes and associated biochemistry. We revealed that NAA50 and HYPK exhibit negative impacts on their binding to NAA15 in vitro and in human cells by inducing NAA15 shifts in opposing directions. NAA50 and HYPK each contribute to NAA10 activity inhibition through structural alteration of the NAA10 substrate binding site.Fourthly, we reported the Cryo-EM structure of hNatB bound to a CoA-αSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis revealed functionally important differences with human NatA and Candida albicans NatB, resolved key hNatB protein determinants for αSyn N-terminal acetylation, and identified important residues for substrate-specific recognition and acetylation by NatB enzymes. Lastly, we report the Cryo-EM structure of S. pombe NatC with a NatE/C-type bi-substrate analogue and inositol hexaphosphate (IP6), and associated biochemistry. We find that all three subunits are prerequisite for normal NatC acetylation activity, IP6 binds tightly to NatC to stabilize the complex, and we determine the molecular basis for IP6-mediated stability of the complex and the overlapping yet distinct substrate profiles of NatC and NatE.

ISBN: 9798738619526Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Catalysis mechanism

The Molecular and Regulatory Mechanism of Multi-Subunit N-Terminal Acetyltransferases.
LDR:03605nmm a2200373 4500 001 2282910
005 20211022115756.5
008 220723s2021 ||||||||||||||||| ||eng d
020 $a 9798738619526
035 $a (MiAaPQ)AAI28319067
035 $a AAI28319067
040 $a MiAaPQ $c MiAaPQ
100 1 $a Deng, Sunbin. $3 3561770
245 1 4 $a The Molecular and Regulatory Mechanism of Multi-Subunit N-Terminal Acetyltransferases.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2021
300 $a 212 p.
500 $a Source: Dissertations Abstracts International, Volume: 82-12, Section: B.
500 $a Advisor: Marmorstein, Ronen.
502 $a Thesis (Ph.D.)--University of Pennsylvania, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a N-terminal acetylation (NTA) is one of the most widespread protein modifications, which occurs on most eukaryotic proteins, but is significantly less common on bacterial and archaea proteins. This modification is carried out by a family of enzymes called N-terminal acetyltransferases (NATs). To date, 12 NATs have been identified, harboring different composition, substrate specificity, and in some cases, modes of regulation. In the first chapter, we review the molecular features of NATs.NatA/E, NatB and NatC, are multi-subunit enzymes, responsible for the majority of eukaryotic protein NTA. Their mechanisms of action and regulation remain poorly understood before this dissertation. In the second chapter, we determined the X-ray crystal structure of yeast NatA/Naa50 as a scaffold to understand coregulation of NatA/Naa50 activity in both yeast and human. We found that Naa50 makes evolutionarily conserved contacts to both the Naa10 and Naa15 subunits of NatA. These interactions promote catalytic crosstalk within the human complex, but do so to a lesser extent in the yeast complex, where Naa50 activity is compromised.Thirdly, we reported the Cryo-EM structures of human NatE and NatE/HYPK complexes and associated biochemistry. We revealed that NAA50 and HYPK exhibit negative impacts on their binding to NAA15 in vitro and in human cells by inducing NAA15 shifts in opposing directions. NAA50 and HYPK each contribute to NAA10 activity inhibition through structural alteration of the NAA10 substrate binding site.Fourthly, we reported the Cryo-EM structure of hNatB bound to a CoA-αSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis revealed functionally important differences with human NatA and Candida albicans NatB, resolved key hNatB protein determinants for αSyn N-terminal acetylation, and identified important residues for substrate-specific recognition and acetylation by NatB enzymes. Lastly, we report the Cryo-EM structure of S. pombe NatC with a NatE/C-type bi-substrate analogue and inositol hexaphosphate (IP6), and associated biochemistry. We find that all three subunits are prerequisite for normal NatC acetylation activity, IP6 binds tightly to NatC to stabilize the complex, and we determine the molecular basis for IP6-mediated stability of the complex and the overlapping yet distinct substrate profiles of NatC and NatE.
590 $a School code: 0175.
650 4 $a Biochemistry. $3 518028
650 4 $a Immunology. $3 611031
650 4 $a Molecular chemistry. $3 1071612
653 $a Catalysis mechanism
653 $a Cryo-EM
653 $a Crystallography
653 $a N-terminal acetylation
653 $a N-terminal acetyltransferase
690 $a 0487
690 $a 0431
690 $a 0982
710 2 $a University of Pennsylvania. $b Chemistry. $3 2096482
773 0 $t Dissertations Abstracts International $g 82-12B.
790 $a 0175
791 $a Ph.D.
792 $a 2021
793 $a English
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28319067