Structural basis of dynamin-mediated membrane fission actin bundling and interaction with binding partners.
动力介导的膜裂变肌动蛋白捆绑和与结合伙伴相互作用的结构基础。
基本信息
- 批准号:10525706
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-16 至 2025-01-15
- 项目状态:未结题
- 来源:
- 关键词:ActinsAddressAffectArginineBindingBiological AssayBiomedical ResearchBiophysicsBundlingCaliberCell fusionCell membraneCell physiologyCellsCellular MembraneCellular biologyChargeComplexCryo-electron tomographyCryoelectron MicroscopyCytoskeletonDefectDevelopmentDynaminElectronsElementsEndocytosisFoundationsGTP BindingGoalsGuanosine TriphosphateGuanosine Triphosphate PhosphohydrolasesHydrolysisIn VitroLengthLipidsLiposomesMalignant NeoplasmsMediatingMembraneMembrane LipidsMentorsMicrofilamentsMissionModelingMolecularMovementNeckNeuropathyOrganismPlayPolymersProcessProlineProline-Rich DomainProtein RegionProteinsRegulationReportingResearchResearch DesignResearch MethodologyResearch PersonnelRoleSH3 DomainsSignal TransductionSiteStructureSystemTertiary Protein StructureTestingTomogramTrainingTubeUnited States National Institutes of HealthVesicleWorkamphiphysinbasebiophysical analysiscareercell motilityconstrictionin vivoinsightintersectin 1mechanical propertiesmutantnovelprogramspublic health relevancereconstitutionreconstructionrecruit
项目摘要
Project Summary/Abstract
Dynamin GTPases have critical roles in mediating endocytosis by wrapping around the neck of budding vesicles
to catalyze membrane fission necessary for the release of nascent vesicles from the plasma membrane.
Recently, we discovered a novel role for dynamin in bundling numerous actin filaments, which has implications
for actin-mediated processes, such as cell-cell fusion and migration. While structural and biophysical studies
have elucidated the mechanism of dynamin assembly and constriction of membranes, several unanswered
questions remain including how dynamin is actually organized and mediates fission within cells, how dynamin
forms the final pre-fission state where it wraps around lipid tubules in a superconstricted state, how dynamin
binds substrates via the proline rich domain (PRD), and how substrate binding regulates dynamin activity. The
long-term objective of this application is to elucidate the mechanism of dynamin-mediated membrane fission
from in vitro and in vivo studies, and to define the mechanism of dynamin interaction with actin and SH3 domain-
containing proteins that recruit dynamin to sites of endocytosis. These objectives will be addressed by the
following specific aims: (1) determine the atomic model of dynamin in the superconstricted prefission state
and define the structure of the PRD; (2) investigate the assembly of the dynamin helical polymer on membranes
within cells; and (3) Elucidate the mechanism of PRD interaction with actin filaments and SH3 domain-containing
binding partners. The rationale for these aims is that: (1) there is no atomic model describing the structural
basis by which dynamin constricts membranes to 3.4 nm in the superconstricted state where spontaneous
hemifission and membrane fission occurs; (2) how dynamin is actually organized in cells has not been reported;
and (3) the structure of the critical PRD and how it binds dynamin substrates including actin, amphiphysin and
intersectin is unknown. The research design and methods are as follows : Aim 1, Apply cryo-electron
microscopy (cryo-EM) to determine the structure of full-length dynamin (containing the PRD) organized around
lipid tubules in the superconstricted state; Aim 2, obtain cryo-electron tomograms and subtomogram averages
of dynamin within cells transfected with a GTPase-deficient dynamin mutant which delays membrane fission and
extends the lifetime of dynamin helices on cellular membranes; Aim 3, obtain the cryo-EM structure of actin
filaments decorated with PRD from dynamin, as well as complexes of dynamin/amphiphysin and
dynamin/intersectin. This work is of
项目总结/文摘
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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John Jimah其他文献
John Jimah的其他文献
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{{ truncateString('John Jimah', 18)}}的其他基金
Structural basis of dynamin-mediated membrane fission actin bundling and interaction with binding partners.
动力介导的膜裂变肌动蛋白捆绑和与结合伙伴相互作用的结构基础。
- 批准号:
10540396 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
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