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Substrate Quality Control in Gram-Negative Outer Membrane Protein Assembly
Substrate Quality Control in Gram-Negative Outer Membrane Protein Assembly
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260311091505.5
- ISBN
- 9798280746770
- DDC
- 572.6
- 서명/저자
- Substrate Quality Control in Gram-Negative Outer Membrane Protein Assembly / Ashton Nicholas Combs
- 발행사항
- [Sl] : Princeton University, 2025
- 형태사항
- 1 electronic resource (152 pages)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisors: Silhavy, Thomas J. Committee members: Gitai, Zemer; Wingreen, Ned S.
- 학위논문주기
- - Ph.D. : Princeton University, 2025.
- 초록/해제
- 요약The outer membrane (OM) of Gram-negative bacteria such as Escherichia coli is an essential organelle that functions as a robust permeability barrier, provides mechanical strength to the cell envelope, and influences cell shape. Nearly all transmembrane proteins in the OM are β-barrel outer membrane proteins (OMPs) that perform diverse and essential functions critical to Gram-negative physiology, including nutrient uptake, toxin efflux, protein secretion, adhesion, and the biogenesis and maintenance of the OM itself. The biogenesis of β-barrel OMPs requires transport by molecular chaperones across the aqueous periplasmic space and assembly into the OM, the latter of which is catalyzed by the β-barrel assembly machine (Bam) complex. Remarkably, both processes occur entirely in the absence of external energy such as ATP and thus often require diverse and sophisticated mechanisms by which their activities are regulated. As the assembly of β-barrel OMPs is both an essential cellular process and occurs at the cell surface, identifying the general mechanisms that ensure rapid and efficient Bam-catalyzed assembly of β-barrel substrates could enable the development of more rational and intricate strategies to better combat Gram-negative pathogens.This thesis employs a series of strategies that deliberately perturb OMP assembly by the Bam complex to identify the general mechanisms that ensure proper quality control of β-barrel substrates. Such efforts reveal a specific role for the periplasmic chaperone Skp in facilitating the direct removal and degradation of assembly-compromised substrates from the Bam complex, wherein Skp functions as a sacrificial adaptor protein and is degraded alongside its bound substrate by the periplasmic protease DegP. We further establish that the Bam complex lipoprotein BamD, like Skp, functions in substrate quality control and is necessary to prevent the improper engagement of β-barrel substrates by the central component of the Bam complex, the β-barrel BamA. Lastly, we show that the simultaneous inactivation of both BamD and Skp activity causes synthetic defects in OM permeability, thus demonstrating a general role for substrate quality control in maintaining the integrity of the OM permeability barrier. Collectively, these results provide insight into the mechanism and physiological significance of substrate quality control functions in Gram-negative OMP assembly.
- 언어주기
- English
- 일반주제명
- Molecular biology
- 일반주제명
- Microbiology
- 일반주제명
- Genetics
- 키워드
- Protein folding
- 기타저자
- Princeton University Molecular Biology
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798280746770
■040 ▼aMiAaPQD▼beng▼cMiAaPQD▼erda
■082 ▼a572.6
■1001 ▼aCombs, Ashton Nicholas▼eauthor.▼0(orcid)0000-0002-0924-9959
■24510▼aSubstrate Quality Control in Gram-Negative Outer Membrane Protein Assembly ▼cAshton Nicholas Combs
■260 ▼a[Sl]▼bPrinceton University▼c2025
■264 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a1 electronic resource (152 pages)
■336 ▼atext▼btxt▼2rdacontent
■337 ▼acomputer▼bc▼2rdamedia
■338 ▼aonline resource▼bcr▼2rdacarrier
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisors: Silhavy, Thomas J. Committee members: Gitai, Zemer; Wingreen, Ned S.
■5021 ▼bPh.D.▼cPrinceton University▼d2025.
■520 ▼aThe outer membrane (OM) of Gram-negative bacteria such as Escherichia coli is an essential organelle that functions as a robust permeability barrier, provides mechanical strength to the cell envelope, and influences cell shape. Nearly all transmembrane proteins in the OM are β-barrel outer membrane proteins (OMPs) that perform diverse and essential functions critical to Gram-negative physiology, including nutrient uptake, toxin efflux, protein secretion, adhesion, and the biogenesis and maintenance of the OM itself. The biogenesis of β-barrel OMPs requires transport by molecular chaperones across the aqueous periplasmic space and assembly into the OM, the latter of which is catalyzed by the β-barrel assembly machine (Bam) complex. Remarkably, both processes occur entirely in the absence of external energy such as ATP and thus often require diverse and sophisticated mechanisms by which their activities are regulated. As the assembly of β-barrel OMPs is both an essential cellular process and occurs at the cell surface, identifying the general mechanisms that ensure rapid and efficient Bam-catalyzed assembly of β-barrel substrates could enable the development of more rational and intricate strategies to better combat Gram-negative pathogens.This thesis employs a series of strategies that deliberately perturb OMP assembly by the Bam complex to identify the general mechanisms that ensure proper quality control of β-barrel substrates. Such efforts reveal a specific role for the periplasmic chaperone Skp in facilitating the direct removal and degradation of assembly-compromised substrates from the Bam complex, wherein Skp functions as a sacrificial adaptor protein and is degraded alongside its bound substrate by the periplasmic protease DegP. We further establish that the Bam complex lipoprotein BamD, like Skp, functions in substrate quality control and is necessary to prevent the improper engagement of β-barrel substrates by the central component of the Bam complex, the β-barrel BamA. Lastly, we show that the simultaneous inactivation of both BamD and Skp activity causes synthetic defects in OM permeability, thus demonstrating a general role for substrate quality control in maintaining the integrity of the OM permeability barrier. Collectively, these results provide insight into the mechanism and physiological significance of substrate quality control functions in Gram-negative OMP assembly.
■546 ▼aEnglish
■590 ▼aSchool code: 0181
■650 4▼aMolecular biology
■650 4▼aMicrobiology
■650 4▼aGenetics
■653 ▼aGram-negative bacteria
■653 ▼aOuter membrane biogenesis
■653 ▼aProtein folding
■653 ▼aProtein quality control
■7102 ▼aPrinceton University▼bMolecular Biology.▼edegree granting institution.
■7201 ▼aSilhavy, Thomas J.▼edegree supervisor.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17356947▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
