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对K-Ras等离子体膜相互作用的时空分析揭示了多个高阶同类分子复合体

Suparna Sarkar-Banerjee¹, Abdallah Sayyed-Ahmad², Priyanka Prakash¹

¹Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston , Houston, Texas 77030, United States.

Journal of the American Chemical Society

|September 2, 2017

概括

Ras GTPases的自我组合是细胞信号的关键. 这项研究揭示了K-Ras4B存在于多个寡合体状态,突变改变了这些分布,提供了对Ras同类体的结构见解.

科学领域:

细胞生物学
生物物理
分子生物学

背景情况:

与等离子膜相关的Ras GTPase是细胞信号的关键调节者.
Ras GTPases,特别是K-Ras4B的结构基础和寡合状态在很大程度上仍未确定.
鉴于K-Ras4B在人类癌症中的频繁突变,了解Ras寡合化是至关重要的.

研究的目的:

确定K-Ras4B寡合体状态的分布 (单体,双体,高阶寡合体).
研究K-Ras4B同类聚合物的结构基础.
分析介面突变如何影响K-Ras4B寡合群体.

主要方法:

活细胞成像技术包括光谱图像相关性 (RICS) 和数量和亮度 (N&B) 分析.
在光漂白后的光回收 (FRAP) 和光相关谱 (FCS).
电子显微镜和模拟分子建模.

主要成果:

野生型G12V K-Ras4B存在于单体,双体和较大的寡体的混合物中.
K101E突变主要是单质的,而K101C/E107C突变显示出对寡质状态的强烈偏好.
K-Ras4B使用两个重叠的接口来形成多种类型的寡合物.

结论:

K-Ras4B可以存在于多个寡合状态,这些种群可以通过界面突变调整.
这项研究为K-Ras同质体的多重性,结构和膜组织提供了第一个详细的结构见解.
这些发现有助于我们更好地理解Ras信号调节及其在癌症中的影响.

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相关概念视频

Small GTPases - Ras and Rho

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:

The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...