Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
基本信息
- 批准号:10392888
- 负责人:
- 金额:$ 64.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Allosteric RegulationAllosteric SiteAnionsArginineBindingBiological AssayCell surfaceCouplesCryoelectron MicroscopyCrystallographyCytoplasmDiseaseDropsElectrophysiology (science)ElectrostaticsElementsEscherichia coliExhibitsExocytosisFamilyFamily memberGlutamate TransporterGlutamatesLobeLysosomesMembrane PotentialsN-terminalNeurotransmittersPhysiologicalPhysiologyProcessPropertyProtein AnalysisProteinsRecyclingRestRoleSialic AcidsSiteStructureSynapsesSynaptic TransmissionSynaptic VesiclesTransmembrane DomainVesicledriving forceextracellularglutamatergic signalingmemberneurotransmissionneurotransmitter releaseneurotransmitter transportpH gradientperiplasmprogramsprotein structure functionprotonationresponsesolutestoichiometrytooluptakevacuolar H+-ATPase
项目摘要
The synaptic vesicle uptake of classical transmitters depends on a H+ electrochemical driving force
(ΔµH+), and generally involves the exchange of cytosolic transmitter for lumenal H+. However, vesicular
glutamate transport relies almost entirely on the electrical component of this gradient (Δψ) rather than
the pH gradient (ΔpH), and undergoes unusual, allosteric regulation by H+ and Cl-. The vesicular
glutamate transporters (VGLUTs) also exhibit an associated Cl- conductance, and the physiological role
of these properties remains unknown. Further, the VGLUTs belong to the solute carrier 17 (SLC17)
family which includes other members that rely on ΔpH rather than Δψ for transport in the opposite
direction from VGLUTs. The long-term objective of this proposal is to understand how the properties of
vesicular glutamate transport contribute to synaptic transmission. The strategy uses structure to
identify the mechanisms common to all family members and understand how their adaptation confers
the specific properties of vesicular glutamate transport. We have determined the first structures of an SLC17 family member, E. coli D-galactonate transporter DgoT, which is closely related in sequence to the VGLUTs. DgoT contains a polar pocket within the N-terminal lobe connected to the periplasm through a putative H+ tunnel evident in the
inwardly oriented structure. An outwardly oriented structure contains galactonate occluded in the
substrate recognition site. The structures predict that delivery of periplasmic H+ to a glutamate in
transmembrane domain (TM) 4 liberates an interacting arginine in TM1 to bind substrate. In contrast to
the VGLUTs but like other SLC17 proteins, DgoT catalyzes H+ cotransport. Although the critical
residues are conserved to the VGLUTs, they thus serve a different function in DgoT. We will now
1) Elucidate the mechanism that couples transport of galactonate to H+ in DgoT.
Using assays for exchange and binding as well as net uptake, we will determine how protonation of
DgoT contributes to substrate recognition. 2) Determine the structural basis for vesicular glutamate transport.
We will use a combination of crystallography and cryo-electron microscopy to determine the structure of
a VGLUT. 3) Elucidate the mechanisms responsible for allosteric regulation of the VGLUTs.
We will leverage the structures as well as the available assays for both DgoT and the mammalian
proteins to understand the allosteric regulation of VGLUTs by H+ and Cl-. We will also use
electrophysiology to assess a channel suggested by the structure, and determine its relationship to
glutamate flux.
突触囊泡对经典递质的摄取依赖于H+电化学驱动力
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ROBERT H EDWARDS其他文献
ROBERT H EDWARDS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ROBERT H EDWARDS', 18)}}的其他基金
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
9258506 - 财政年份:2015
- 资助金额:
$ 64.24万 - 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
9920217 - 财政年份:2015
- 资助金额:
$ 64.24万 - 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
8964141 - 财政年份:2015
- 资助金额:
$ 64.24万 - 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
- 批准号:
10614384 - 财政年份:2015
- 资助金额:
$ 64.24万 - 项目类别:
相似海外基金
Allosteric site prediction and transmission of functional residues with atomistic graph analysis
通过原子图分析进行功能残基的变构位点预测和传递
- 批准号:
2859072 - 财政年份:2020
- 资助金额:
$ 64.24万 - 项目类别:
Studentship
Creation of novei anticancer lead compounds targeting the allosteric site of c-Met kinase
创建针对 c-Met 激酶变构位点的新型抗癌先导化合物
- 批准号:
16K08327 - 财政年份:2016
- 资助金额:
$ 64.24万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Studying how a general allosteric site regulates protein kinase function
研究一般变构位点如何调节蛋白激酶功能
- 批准号:
8595027 - 财政年份:2013
- 资助金额:
$ 64.24万 - 项目类别:
Studying how a general allosteric site regulates protein kinase function
研究一般变构位点如何调节蛋白激酶功能
- 批准号:
8704718 - 财政年份:2013
- 资助金额:
$ 64.24万 - 项目类别:
Studying how a general allosteric site regulates protein kinase function
研究一般变构位点如何调节蛋白激酶功能
- 批准号:
8874171 - 财政年份:2013
- 资助金额:
$ 64.24万 - 项目类别:
STRUC DETERMINATION OF METAL-SUBSTITUTED & ALLOSTERIC SITE VARIANTS OF H INFLU
金属取代物的结构测定
- 批准号:
7955561 - 财政年份:2009
- 资助金额:
$ 64.24万 - 项目类别:
EXAMINATION OF ALLOSTERIC SITE OF SEROTONIN TRANSPORTER USING TRANSGENIC MICE
使用转基因小鼠检查血清素转运蛋白的变构位点
- 批准号:
7715783 - 财政年份:2008
- 资助金额:
$ 64.24万 - 项目类别:
STRUC DETERMINATION OF METAL-SUBSTITUTED & ALLOSTERIC SITE VARIANTS OF H INFLU
金属取代物的结构测定
- 批准号:
7721325 - 财政年份:2008
- 资助金额:
$ 64.24万 - 项目类别:
ALLOSTERIC SITE STRUCTURES OF CARDIOVASCULAR CHANNELS
心血管通道的变构位点结构
- 批准号:
7215384 - 财政年份:2007
- 资助金额:
$ 64.24万 - 项目类别:
EXAMINATION OF ALLOSTERIC SITE OF SEROTONIN TRANSPORTER USING TRANSGENIC MICE
使用转基因小鼠检查血清素转运蛋白的变构位点
- 批准号:
7562646 - 财政年份:2007
- 资助金额:
$ 64.24万 - 项目类别: