细胞功能依赖于错综复杂的信号作用网络，这些网络包含多个蛋白信号作用核心，它们与几个合作伙伴发生相互作用，来调控多个下游信号。对这样一个核心（即腺病毒“早期区域1A” (E1A) 致癌蛋白）所做的这项研究，利用新颖的单分子FRET测定来克服整合问题，直接探测E1A与两个关键合作伙伴的变构相互作用。这些结果显示了一个引人注目的合作性调制方式，它是由多种相互作用及E1A相互作用主题（interaction motifs）的有无调控的。
变构相互作用的这样一种调制方式，可能是内在紊乱的核心蛋白（hub proteins）的一个共同特征。（生物谷Bioon.com）
生物谷推荐英文摘要:
Nature doi:10.1038/nature12294
Modulation of allostery by protein intrinsic disorder
Allan Chris M. Ferreon,Josephine C. Ferreon,Peter E. Wright & Ashok A. Deniz
Allostery is an intrinsic property of many globular proteins and enzymes that is indispensable for cellular regulatory and feedback mechanisms. Recent theoretical and empirical observations indicate that allostery is also manifest in intrinsically disordered proteins, which account for a substantial proportion of the proteome . Many intrinsically disordered proteins are promiscuous binders that interact with multiple partners and frequently function as molecular hubs in protein interaction networks. The adenovirus early region 1A (E1A) oncoprotein is a prime example of a molecular hub intrinsically disordered protein. E1A can induce marked epigenetic reprogramming of the cell within hours after infection, through interactions with a diverse set of partners that include key host regulators such as the general transcriptional coactivator CREB binding protein (CBP), its paralogue p300, and the retinoblastoma protein (pRb; also called RB1). Little is known about the allosteric effects at play in E1A–CBP–pRb interactions, or more generally in hub intrinsically disordered protein interaction networks. Here we used single-molecule fluorescence resonance energy transfer (smFRET) to study coupled binding and folding processes in the ternary E1A system. The low concentrations used in these high-sensitivity experiments proved to be essential for these studies, which are challenging owing to a combination of E1A aggregation propensity and high-affinity binding interactions. Our data revealed that E1A–CBP–pRb interactions have either positive or negative cooperativity, depending on the available E1A interaction sites. This striking cooperativity switch enables fine-tuning of the thermodynamic accessibility of the ternary versus binary E1A complexes, and may permit a context-specific tuning of associated downstream signalling outputs. Such a modulation of allosteric interactions is probably a common mechanism in molecular hub intrinsically disordered protein function.
