Mechanisms of Lipid Droplet Formation
脂滴形成机制
基本信息
- 批准号:10685392
- 负责人:
- 金额:$ 42.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcyltransferaseAddressAdoptedAreaAtherosclerosisBSCL2 geneBindingBinding ProteinsBiochemicalBiochemistryBiologyCell physiologyCellsCellular biologyComplexCryoelectron MicroscopyCytoplasmCytosolDataEmulsionsEndoplasmic ReticulumEnergy MetabolismEnsureEnzymesEukaryotic CellFaceFatty acid glycerol estersGenerationsGlycerolHumanIn VitroInvestigationLipid BilayersLipid InclusionLipidsMembraneMembrane LipidsMetabolicMetabolic DiseasesModelingMolecularMolecular ConformationMolecular StructureNon-Insulin-Dependent Diabetes MellitusObesityOrganellesPhase TransitionPhospholipidsProcessProteinsResearchSet proteinSiteStructureTestingTriglyceridesWorkexperimental studyfatty liver diseasein vitro testinginsightmembrane synthesismolecular dynamicsmonolayermonomernovel therapeuticsparticlepreventprotein complexprotein functionreconstitutionsimulationstructural biologytomographytool
项目摘要
PROJECT SUMMARY
Lipid droplets (LDs) are ubiquitous monolayer-bound organelles that function in cellular lipid storage (for metabolic energy
or membrane synthesis). LDs form from the ER, but how LDs are formed remains unknown and is a central question for the
field. The current model indicates that neutral lipids, such as triacylglycerols (TG), are synthesized in the ER and released
into the bilayer. At a critical concentration, TGs de-mix from the phospholipid bilayer in a phase transition that forms
nascent LDs that bud toward the cytosol. We hypothesize that proteins are essential to ensure this process occurs in a
defined manner and to prevent the formation of “ectopic” and potentially dysfunctional LDs, disrupting ER and cell
function. Specifically, two ER proteins – seipin and lipid droplet assembly factor 1 (LDAF1) – operate in the lipid droplet
assembly complex (LDACs) in the ER to form LDs. Both proteins form an oligomeric assembly with seipin forming a ring
of 10-12 subunits and an equal number of LDAF1 occupying the middle of the ring. While we have identified components
of the LD formation machinery and gained some insight into their structures, how these proteins function to facilitate LD
formation remains mostly a mystery. Here we propose to utilize the latest tools and approaches, including biochemistry,
structural biology, molecular simulations, and cell biology, to address the following questions: How and where is TG made
relative to LDACs? What are the molecular structures of the seipin/LDAF1 LDACs? How do these oligomeric complexes
assemble/disassemble? Where do LDACs localize in cells? How do they function to organize LD formation? We will
address these questions by completing four specific aims. Aim 1 will address the mechanism of TG synthesis in the ER by
the DGAT1 enzyme. We will expand on our recent elucidation of the molecular structure of human DGAT1, combining
molecular dynamics and biochemical experiments to elucidate the precise mechanism of TG generation and determine how
TG is released into the ER membrane for LD formation. Aim 2 will determine how and where LD assembly complexes
assemble in cells to form LDs. We will determine the relationship of TG synthesis to LDACs, whether seipin/LDAF1
LDACs localize to ER tubules and how they assemble. Aim 3 will focus on elucidating the molecular structure of the
seipin/LDAF1 LDAC in vitro and in cells. We will utilize cell and structural biology approaches, including cryo-EM and
cryo-ET to test the hypothesis that seipin and LDAF1 form a ring structure with LDAF1 in center and that these LDACs
form at areas of membrane curvature (tubules) where the structure may adopt dynamic conformations and activate of the
complex. Aim 4 will determine the molecular function of the seipin/LDAF1 LDAC in vitro and in molecular dynamics
simulations. We will reconstitute LD formation to test the hypothesis that the seipin/LDAF1 LDAC catalyzes phase
transition of TG in the membrane, ensuring LDs form at these designated formation sites. Successful completion of these
aims will advance the molecular understanding of a fundamental process central to energy metabolism and provide
information on the mechanistic underpinning of many metabolic diseases, such as obesity, atherosclerosis, and fatty liver
disease.
项目总结
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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{{ truncateString('ROBERT V FARESE', 18)}}的其他基金
Lipotoxic Protective Response of the Endoplasmic Reticulum
内质网的脂毒性保护反应
- 批准号:
10176932 - 财政年份:2021
- 资助金额:
$ 42.48万 - 项目类别:
Lipotoxic Protective Response of the Endoplasmic Reticulum
内质网的脂毒性保护反应
- 批准号:
10376867 - 财政年份:2021
- 资助金额:
$ 42.48万 - 项目类别:
Lipotoxic Protective Response of the Endoplasmic Reticulum
内质网的脂毒性保护反应
- 批准号:
10706013 - 财政年份:2021
- 资助金额:
$ 42.48万 - 项目类别:
Lipotoxic Protective Response of the Endoplasmic Reticulum
内质网的脂毒性保护反应
- 批准号:
10551904 - 财政年份:2021
- 资助金额:
$ 42.48万 - 项目类别:
Lipid Droplets and Transcriptional Regulation of Metabolism
脂滴和代谢的转录调控
- 批准号:
10696383 - 财政年份:2020
- 资助金额:
$ 42.48万 - 项目类别:
Lipid Droplets and Transcriptional Regulation of Metabolism
脂滴和代谢的转录调控
- 批准号:
10356853 - 财政年份:2020
- 资助金额:
$ 42.48万 - 项目类别:
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