SUGAR TRANSPORTER OLIGOMERIC STRUCTURE AND FUNCTION
糖转运蛋白寡聚结构和功能
基本信息
- 批准号:3246405
- 负责人:
- 金额:$ 10.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-05-01 至 1995-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This proposal represents a continuing effort by our laboratory to
understand the mechanism of protein-mediated sugar transport across cell
membranes. The broad goal of this proposal is to understand how sugar
transport protein oligomerization occurs and how transport protein
oligomerization affects transport function. These studies will assist in
our long term goals of understanding the physical basis and the cellular
regulation of sugar transport and could ultimately be of value in the
management of disordered states such as diabetes.
Our studies show that the human erythrocyte sugar transport system exists
in two catalytically active forms: as a tetramer (major species) and as a
dimer (minor species) of GLUT1 proteins. The oligomeric state of the
sugar transport protein determines the catalytic properties of transport.
Specific Aim 1 asks whether purified tetrameric GLUT1, like
erythrocyte-resident GLUT1, is a multisite, allosteric transporter. Our
studies suggest that the arrangement of substrate binding sites in
tetrameric and dimeric GLUT1 is different. Tetrameric GLUT1 appears to
behave as 2 "two-site carriers" that simultaneously expose both sugar
influx and sugar efflux sites to substrate. Dimeric GLUT1 behaves as 2
independent "simple carriers" that alternately expose sugar influx and
sugar efflux sites to substrate. We test this hypothesis by asking
whether purified, tetrameric or dimeric GLUT1 can bind substrates at
sugar influx and at sugar efflux sites simultaneously. If our hypothesis
is correct, only the tetramer should expose both sites simultaneously.
Specific Aim 2 asks if the cryptic cysteines in tetrameric GLUT1 are
present as disulfides. Tetrameric GLUT1 contains only 2 free cysteines
per GLUT1 monomer, is converted to dimer by reductant but is not two
disulfide-linked dimers. Dimeric GLUT1 contains 6 free cysteines per
GLUT1 monomer. We use differential carboxymethylation procedures and
peptide mapping to identify the cryptic cysteines of the tetramer and to
determine whether the cryptic cysteines are internal disulfides, mixed
disulfides or are fatty acylated. Specific Aim 3 asks what role the
cryptic cysteines of tetrameric GLUT1 play in tetramerization of GLUT1.
If modification of a specific cysteine causes tetramerization of GLUT I,
deletion of the cysteine should prevent tetramer formation. Each of the
6 GLUT1 cysteines will be mutated. The effects of these mutations on
GLUT1 oligomeric structure, ligand binding and sugar transport will be
evaluated. If successful, these studies will greatly assist in our long
term goal of understanding sequence-specific determinants of sugar
transporter higher order structure and function.
这项建议代表了我们实验室继续努力
了解蛋白质介导的糖跨细胞转运的机制
膜。这项提议的主要目标是了解糖是如何
转运蛋白齐聚的发生以及转运蛋白是如何
寡聚作用影响转运功能。这些研究将有助于
我们的长期目标是了解物理基础和细胞
对糖运输的调节,并最终可能在
对糖尿病等紊乱状态的管理。
我们的研究表明,人类红细胞糖运输系统是存在的
以两种催化活性形式:作为四聚体(主要物种)和作为
GLUT1蛋白的二聚体(次要物种)。的低聚状态
糖转运蛋白决定了转运蛋白的催化性质。
特定目标1问纯化的四聚体GLUT1是否像
红细胞驻留的GLUT1是一种多位点变构转运蛋白。我们的
研究表明,底物结合位点的排列
四聚体和二聚体GLUT1是不同的。四聚体GLUT1似乎
充当两个同时暴露两种糖的“双部位携带者”
底物的内流和糖流出部位。二聚体GLUT1表现为2
独立的“简单载体”交替暴露糖的流入和
糖外流到底物的位置。我们通过询问以下问题来检验这一假设
无论是纯化的、四聚的还是二聚的GLUT1都能结合底物
糖流入和糖外排部位同时存在。如果我们的假设
是正确的,只有四聚体应该同时暴露两个位置。
特定目标2询问四聚体GLUT1中隐藏的半胱氨酸是否
以二硫化物的形式出现。四聚体GLUT1只含有2个游离半胱氨酸
每个GLUT1单体被还原剂转化为二聚体,但不是两个
二硫键连接的二聚体。二聚体GLUT1每个含有6个游离半胱氨酸
Glut1单体。我们使用不同的羧甲基化程序
用肽图鉴定四聚体的隐形半胱氨酸
确定隐蔽的半胱氨酸是否是内部二硫化物,混合
二硫化物或脂肪酰化。具体目标3问的是什么角色
四聚体GLUT1的隐型半胱氨酸在GLUT1的四聚反应中发挥作用。
如果特定半胱氨酸的修饰导致GLUT I的四聚化,
半胱氨酸的缺失应该会阻止四聚体的形成。每一位
6个GLUT1半胱氨酸将发生突变。这些突变对人类健康的影响
Glut1的寡聚结构、配体结合和糖的运输
已评估。如果成功,这些研究将极大地帮助我们
理解糖的序列特异性决定因素的术语目标
运输机更高级的结构和功能。
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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ANTHONY CARRUTHERS其他文献
ANTHONY CARRUTHERS的其他文献
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{{ truncateString('ANTHONY CARRUTHERS', 18)}}的其他基金
SUGAR TRANSPORTER OLIGOMERIC STRUCTURE AND FUNCTION
糖转运蛋白寡聚结构和功能
- 批准号:
2905478 - 财政年份:1992
- 资助金额:
$ 10.48万 - 项目类别:
SUGAR TRANSPORTER OLIGOMERIC STRUCTURE AND FUNCTION
糖转运蛋白寡聚结构和功能
- 批准号:
3246404 - 财政年份:1992
- 资助金额:
$ 10.48万 - 项目类别:
How glucose transporter structure affects its function
葡萄糖转运蛋白结构如何影响其功能
- 批准号:
8733151 - 财政年份:1992
- 资助金额:
$ 10.48万 - 项目类别:
SUGAR TRANSPORTER OLIGOMERIC STRUCTURE AND FUNCTION
糖转运蛋白寡聚结构和功能
- 批准号:
2144152 - 财政年份:1992
- 资助金额:
$ 10.48万 - 项目类别:
SUGAR TRANSPORTER OLIGOMERIC STRUCTURE AND FUNCTION
糖转运蛋白寡聚结构和功能
- 批准号:
2430197 - 财政年份:1992
- 资助金额:
$ 10.48万 - 项目类别:
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