Allosteric coupling between sites in intrinsically disordered proteins (IDPs) can be either positive or negative and does not require mechanical linkage. Instead, it arises through perturbations of the energetic balance by binding events at individual sites. A letter published in Nature this week describes a single-molecule version of Fluorescence Resonance Energy Transfer (smFRET) used to elucidate the details of adenoviral protein E1A binding.
More on single-molecule biochemistry: Dulin et al., “Studying genomic processes at the single-molecule level: introducing the tools and applications”. Nature Reviews Genetics, vol 14, pp. 9‒14 (2013).
As usual with IDPs, their structural versatility produces odd results. A rarity in biology, the negative cooperativity of the E1A protein rather than decrease its binding potential, increases its binding promiscuity.
E1A acts as a “molecular hub”, and its negative cooperativity increases the population of intermediate binding states (binary complexes) and facilitating their interaction with other partners. This responsivity to a wide range of stimuli allows context-dependent modulation of the different molecular species that aid viral E1A in subverting host cellular mechanisms.
Horwitz et al., “Adenovirus Small e1a Alters Global Patterns of Histone Modification. Science, vol 321, pp. 1084‒5 (2008).
Ferrari et al., “Epigenetic Reprogramming by Adenovirus e1a”. Ibid., pp. 1086‒8 (2008).
Multiple layers of regulation can be imposed on the E1A hub, depending on which domains of E1A are available for interaction with CBP/p300 and pRb, permitting the cooperativity of the system to be fine-tuned over a broad concentration range.Our results indicate that intrinsically disordered protein systems can be tuned to optimize population distributions and cellular outcome by changing the available binding sites.
The authors also note a recent theoretical study (Motlagh et al., 2012) which showed that
Allosteric ensembles associated with intrinsic protein disorder can upregulate or downregulate activity in response to different physiological stimuli, a feature of E1A that both activates and represses gene expression.
Similar to alternative splicing in modulating function by way of modulating interactions at physical sites, both allowing viral genomes to remain small yet potent, the modulation of allostery is another way life pulls off such high degrees of functional complexity even on the nanoscale.
Ferreon et al., “Modulation of allostery by protein intrinsic disorder”. Nature, vol 498, pp. 390‒394 (2013).

Allosteric coupling between sites in intrinsically disordered proteins (IDPs) can be either positive or negative and does not require mechanical linkage. Instead, it arises through perturbations of the energetic balance by binding events at individual sites. A letter published in Nature this week describes a single-molecule version of Fluorescence Resonance Energy Transfer (smFRET) used to elucidate the details of adenoviral protein E1A binding.

As usual with IDPs, their structural versatility produces odd results. A rarity in biology, the negative cooperativity of the E1A protein rather than decrease its binding potential, increases its binding promiscuity.

E1A acts as a “molecular hub”, and its negative cooperativity increases the population of intermediate binding states (binary complexes) and facilitating their interaction with other partners. This responsivity to a wide range of stimuli allows context-dependent modulation of the different molecular species that aid viral E1A in subverting host cellular mechanisms.

Multiple layers of regulation can be imposed on the E1A hub, depending on which domains of E1A are available for interaction with CBP/p300 and pRb, permitting the cooperativity of the system to be fine-tuned over a broad concentration range.

Our results indicate that intrinsically disordered protein systems can be tuned to optimize population distributions and cellular outcome by changing the available binding sites.

The authors also note a recent theoretical study (Motlagh et al., 2012) which showed that

Allosteric ensembles associated with intrinsic protein disorder can upregulate or downregulate activity in response to different physiological stimuli, a feature of E1A that both activates and represses gene expression.

Similar to alternative splicing in modulating function by way of modulating interactions at physical sites, both allowing viral genomes to remain small yet potent, the modulation of allostery is another way life pulls off such high degrees of functional complexity even on the nanoscale.

Ferreon et al., “Modulation of allostery by protein intrinsic disorder”. Nature, vol 498, pp. 390‒394 (2013).

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