Membrane Protein Folding and Assembly
膜蛋白折叠和组装
基本信息
- 批准号:10411888
- 负责人:
- 金额:$ 39.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseBiologicalBiological ModelsCellsChimeric ProteinsCryoelectron MicroscopyCystic FibrosisCytoplasmCytoplasmic TailDiseaseDrug TargetingElectronsEngineeringEscherichia coliFoundationsGoalsGrowthHydrophobicityLipidsMembraneMembrane ProteinsMethodsMotorPaperPathway interactionsPeptide HydrolasesProcessProtein FamilyProteinsSignal Recognition ParticleStructureSystemTemperatureWorkexperimental studyhuman diseasein vivoin vivo Modelinsightmolecular dynamicsnanodiskperiplasmprotein foldingprotein misfoldingsecretion process
项目摘要
Save date: 15 Jan 2020, 22:40
ABSTRACT
Membrane Protein Folding and Assembly
Many human diseases, such as cystic fibrosis, result from misfolding of membrane proteins
(MPs) during their synthesis and targeting. It is therefore important to understand the principles
and mechanism of MP folding and assembly. A largely unexplored part of the problem is to
understand folding in the context of the cellular milieu. Toward that goal, we are studying the
targeting, secretion, and insertion of membrane proteins along the so-called SecA post-
translational pathway of living Escherichia coli. We have shown that the SecA motor ATPase,
a significant drug target, can insert single-span membrane proteins (S-SMPs) across the E. coli
inner membrane. This simplified in vivo model system eliminates the many unanswered
questions about the folding of multi-span MPs along the signal recognition particle (SRP)
pathway, because we gain direct access to the translocon-bilayer partitioning process.
We have engineered two different chimeric protein families for probing systematically S-
SMP stability using TM segments of the form GGPG-H-GPGG (used in an earlier study to
determine a biological hydrophobicity scale using a cell-free eukaryotic system). To determine
stabilities, we have developed methods for cleaving TM segments in vivo via native
intramembrane proteases. We have discovered that many S-SMPs are stable across the
membrane only because their periplasmic & cytoplasmic domains cannot cross the membrane.
We have also discovered that translocon-to-membrane transfer energetics are not equal to
membrane-to-cytoplasm transfer energetics and that stability depends upon growth
temperature. An important aspect of our work is the use of Molecular Dynamics simulations in
concert with experiments to understand the dynamics of the SecYEG translocon. Little is known
about SecA function at the atomic level despite hundreds of papers on the subject. Calling
upon our lab’s expertise in lipid-protein interactions, we have laid the foundation for electron
cryomicroscopic (cryo-EM) studies of the structure of SecA bound to lipid nanodiscs. Our
ambition is to obtain a complete structural view of the SecA-guided secretion process.
SWhite_Abstract_MIRA_2020.docx, 15 January 2020
保存日期:2020年1月15日22:40
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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STEPHEN H. WHITE其他文献
STEPHEN H. WHITE的其他文献
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{{ truncateString('STEPHEN H. WHITE', 18)}}的其他基金
Proj 2:Neutron Diffraction Studies of Voltage Sensor Molecules in Lipid Bilayers
项目 2:脂质双层中电压传感器分子的中子衍射研究
- 批准号:
7625288 - 财政年份:2009
- 资助金额:
$ 39.25万 - 项目类别:
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