Modulation of allostery by protein intrinsic disorder
By A. C. Ferreon, J. Ferreon, Peter E. Wright, A. Deniz. 2013
314 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology
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In Genetics
In Molecular Biology
- Gábor Erdös
- Zsuzsanna Dosztányi
- Bálint Mészáros
- Vladimir N Uversky
- Lukasz Kurgan
- Fanchi Meng
- Zhenling Peng
- Jörg Gsponer
Citations in the corpus
- IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding (2018, background): “E1A is a largely disordered protein (51), which is essential for forcing the host cell into S phase via modulation of the Rb1 / E2F1 pathway (52) and the inhibition of apoptosis via modulation of p53 degradation (53).”
- Structured states of disordered proteins from genomic sequences (2016, unknown): “, 1963; Perutz, 1970) and is associated with diverse cellular functions including metabolism, gene regulation, signaling, and molecular transport, spurring growing interest in so-called disordered and low-complexity sequences (Bah et al., 2015; Ferreon et al., 2013; Motlagh et al., 2014; Tokuriki an”