在高亲密性蛋白质-蛋白质相互作用中诱导内在疾病的后果
Grigorios Papadakos1, Amit Sharma2, Lorna E Lancaster3
1†Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
Journal of the American Chemical Society
|April 10, 2015
概括
通过突变诱导蛋白质疾病显著削弱结合亲和力,尽管保持复杂的结构. 这突出了与蛋白质识别内在障碍相关的动力学和热力学成本.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 分子生物物理学 分子生物物理学
背景情况:
- 蛋白质对蛋白质的识别对于生物过程至关重要.
- 蛋白质内在障碍 (IDP) 起到不同的作用,但其对结合动力学和热力学的影响仍在争论中.
- 高 afinity 的 colicin E3 rRNase 域-Im3 复合体 (K(d) ≈10(-12) M) 作为一个模型系统.
研究的目的:
- 为了研究诱导高亲和复合体的蛋白质合作伙伴内在障碍的动力学和热力学后果.
- 确定单个突变如何影响蛋白质结构,结合亲和力和相互作用动态.
主要方法:
- 局部导向的突变生成,以创建一个内在无序的蛋白质变体 (E3rRNase(IDP)).
- 生物物理测量 (例如,ITC,SPR,光谱) 来表征结合.
- 稳定状态前的动力学分析,以剖析关联率和解离率.
主要成果:
- 一个单一的氨酸突变 (Tyr507) 将折叠的素E3rRNase域转化为IDP (E3rRNase(IDP)).
- E3 rRNase ((IDP) 结合Im3在体质上,形成一个复杂的结构,几乎与野生类型相同.
- 结合亲和力下降了4个数量级,主要是由于结合率较慢.
- 热力学参数表明,复杂的形成时,有显著的混乱到秩序的过渡.
结论:
- 内在疾病可以通过单个突变诱导到稳定的蛋白质领域.
- 虽然IDP可以形成稳定的复合体,但诱导障碍会产生相当大的动力和热力学惩罚.
- 这项研究量化了内在障碍的潜在优势与蛋白质识别中的能量成本之间的权衡.
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