通过部分展开过渡来激活Par-6 PDZ的Allosteric激活
Dustin S Whitney1, Francis C Peterson, Evgenii L Kovrigin
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
Journal of the American Chemical Society
|May 28, 2013
概括
分区缺陷6 (Par-6) 蛋白质的灵活性对其功能至关重要. 意想不到的是,PDZ域的部分展开促进了全调节,揭示了蛋白质动态的新机制.
科学领域:
- 蛋白质的生物化学 蛋白质的生物化学
- 分子生物学分子生物学
- 结构生物学是结构生物学.
背景情况:
- 蛋白质平衡原生和展开状态的功能,有时牺牲稳定性灵活性.
- 分区缺陷6 (Par-6) 蛋白通过其Cdc42/Rac相互作用结合PSD-95/Dlg/ZO-1 (CRIB-PDZ) 模块来调节Par极性复合体.
- 在Par-6中的Allosteric调节涉及CRIB:PDZ接口的重排,影响PDZ连接体结合.
研究的目的:
- 在全调节期间调查Par-6 PDZ域的动力学和热力学稳定性.
- 阐明第六部分L164/K165侧链交换背后的结构机制.
- 探索蛋白质展开在Par-6的全性机制中的作用.
主要方法:
- 微秒到毫秒时间尺度的动态测量.
- 在PDZ域内分析局部结构稳定性.
- 对PDZ领域的热力学稳定性评估.
主要成果:
- 在Par-6中L164/K165侧链交换需要比预期更大的结构重组.
- PDZ 域表现出适度的热力学稳定性 (∼3 kcal/mol),由 CRIB 域相互作用进一步降低.
- PDZ域的部分展开破坏了三级接触,使得L/K开关对于全激活至关重要.
结论:
- 部分原生状态的展开是Par-6全性机制的组成部分.
- 这一发现表明,原生状态展开可能是其他边缘稳定蛋白质功能调节的一般机制.
- 对于催化和结合至关重要的蛋白质灵活性可以通过受控的部分展开事件来实现.
相关概念视频
01:58Cooperative Allosteric Transitions
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
01:58Cooperative Allosteric Transitions
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
01:58Cooperative Allosteric Transitions
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
01:08Allosteric Regulation
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...