A dynamic hydrophobic core orchestrates allostery in protein kinases

Kim, Jonggul; Ahuja, Lalima G.; Chao, Fa-An; Xia, Youlin; McClendon, Christopher L.; Kornev, Alexandr P.; Taylor, Susan S.; Veglia, Gianluigi

doi:10.1126/sciadv.1600663

Cited by 101 publications

(161 citation statements)

References 55 publications

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“…These studies showed the importance of the hydrophobic core in distinct allosteric responses. A more recent study of protein kinase A also demonstrated the importance of the hydrophobic protein core in allostery [38]. The hydrophobic core of PTP1B exhibits species conservation among PTP1B enzymes; however, many of the hydrophobic residues identified in our work as part of the allosteric network are not conserved among human tyrosine-specific phosphatases [22].…”

Section: Resultsmentioning

confidence: 71%

Leveraging Reciprocity to Identify and Characterize Unknown Allosteric Sites in Protein Tyrosine Phosphatases

Cui

Beaumont

Ginther

et al. 2017

Journal of Molecular Biology

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Drug-like molecules targeting allosteric sites in proteins are of great therapeutic interest; however, identification of potential sites is not trivial. A straightforward approach to identify hidden allosteric sites is demonstrated in protein tyrosine phosphatases (PTP) by creation of single alanine mutations in the catalytic acid loop of PTP1B and VHR. This approach relies on the reciprocal interactions between an allosteric site and its coupled orthosteric site. The resulting NMR chemical shift perturbations (CSPs) of each mutant reveal clusters of distal residues affected by acid loop mutation. In PTP1B and VHR, two new allosteric clusters were identified in each enzyme. Mutations in these allosteric clusters detrimentally altered phosphatase activity with reductions in kcat/KM ranging from 30% to nearly 100-fold. This work outlines a simple method for identification of new allosteric sites in PTP, and given the basis of this method in thermodynamics, it is expected to be generally useful in other systems.

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Section: Resultsmentioning

confidence: 71%

Leveraging Reciprocity to Identify and Characterize Unknown Allosteric Sites in Protein Tyrosine Phosphatases

Cui

Beaumont

Ginther

et al. 2017

Journal of Molecular Biology

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“…This method provided atomic‐level insight into how distal amino acid substitutions, like G121V and S148A, can propagate their effects throughout the enzyme. Similar types of network analyses have contributed to our understanding in many other enzyme systems …”

Section: Enzymes As Amino Acid Interaction Networkmentioning

confidence: 88%

“…Similar types of network analyses have contributed to our understanding in many other enzyme systems. [101][102][103][104][105][106][107] These long-range networks may also offer means through which enzymes communicate in multi-enzyme complexes. 97 For example, we used NMR chemical shift covariance analysis 108,109 among a series of sitedirected protein variants to identify amino acid interaction networks in the alpha subunit of E. coli tryptophan synthase (aTS).…”

Section: Enzymes As Amino Acid Interaction Networkmentioning

confidence: 99%

Engineered control of enzyme structural dynamics and function

2018

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Enzymes undergo a range of internal motions from local, active site fluctuations to large-scale, global conformational changes. These motions are often important for enzyme function, including in ligand binding and dissociation and even preparing the active site for chemical catalysis. Protein engineering efforts have been directed towards manipulating enzyme structural dynamics and conformational changes, including targeting specific amino acid interactions and creation of chimeric enzymes with new regulatory functions. Post-translational covalent modification can provide an additional level of enzyme control. These studies have not only provided insights into the functional role of protein motions, but they offer opportunities to create stimulus-responsive enzymes. These enzymes can be engineered to respond to a number of external stimuli, including light, pH, and the presence of novel allosteric modulators. Altogether, the ability to engineer and control enzyme structural dynamics can provide new tools for biotechnology and medicine.

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“…One may then speculate that these charged residues, which are perturbed by binding, trigger redistribution of the internal electrostatic interaction energy and thus play a role in CAP allosteric function. Protein kinases were also proposed to be dynamics-driven allosteric proteins (16), where allostery is orchestrated by a dynamic hydrophobic core (17). Like the butterfly effect, a single mutation in cancer can remodel the whole cell (18).…”

mentioning

confidence: 99%

Energetic redistribution in allostery to execute protein function

Liu

Nussinov

2017

Proc. Natl. Acad. Sci. U.S.A.

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A perturbation at one site of the protein could cause an effect at a distant site. This important biological phenomenon, termed the "allosteric effect," is essential for protein regulation and cell signaling, playing an important role in cellular function. Its fundamental functional significance has inspired numerous works aiming to understand how allostery works. Allostery can involve large, or unobserved, subtle (mainly side-chain) conformational changes (1). Conformational changes are driven by enthalpy. The term "dynamic allostery" was coined by Cooper and Dryden in the early 1980s to describe allostery "even in the absence of a macromolecular conformational change" (2). Cooper and Dryden argued that dynamic allostery is primarily an entropy effect. However, numerous works have been published over the last 20 y taking "dynamic allostery" to imply a complete absence of conformational change because the authors did not observe such changes (1). Importantly, "dynamic allostery" without observable conformational changes is still ruled by a population shift between two "distinct" states where a new energetic redistribution favorable for the allosteric (functional) state is either dominated by entropy, enthalpy, or both. Few studies questioned whether enthalpy plays a role in dynamic allostery as well (1). In PNAS, Kumawat and Chakrabarty (3) demonstrate that indeed even in dynamic allostery enthalpy plays a role by redistributing internal energies, especially electrostatic interaction energies, among residues upon perturbation (Fig. 1).Electrostatics is an established player in function. Decades ago, Warshel (4) and Warshel et al. (5) demonstrated its critical role in protein catalysis and Perutz (6) in allostery. Recently, rearrangements of electrostatic networks were reported for conformationally driven allostery (7,8). The report of hidden electrostatic interactions in dynamic allostery in PNAS (3) argues that redistribution of electrostatic interaction energy could be universal in allosteric proteins, with or without significant conformational change.Proteins embrace redistribution of electrostatic interaction energies to execute their functions. For example, myosin, a motor protein, binds to the negatively charged ATP, which redistributes the electrostatic bond network, thus altering the charge of the actin-binding site, leading to myosin's dissociation from actin (7). Thus, myosin redistributes electrostatic interaction energy in allostery to execute its function of dissociation from actin.The PDZ domain protein is a well-known cell signaling protein. The major functions of PDZ domains include recognition of the disordered C-terminal peptide motifs of hundreds of receptors and ion-channel proteins, dimerization with other modular domains, and phospholipid binding. As a dynamic regulator of cell signaling, PDZ function can be modulated allosterically (9). In the PDZ3 domain protein, the peptide recognition site is located at the hydrophobic β2-α2 region. Mutations of distal residues on the PDZ3 domain or del...

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A dynamic hydrophobic core orchestrates allostery in protein kinases

Abstract: The synchronized motions of inner core residues allosterically modulate the activity of the protein kinase A catalytic subunit.

Cited by 101 publications

References 55 publications

Leveraging Reciprocity to Identify and Characterize Unknown Allosteric Sites in Protein Tyrosine Phosphatases

Leveraging Reciprocity to Identify and Characterize Unknown Allosteric Sites in Protein Tyrosine Phosphatases

Engineered control of enzyme structural dynamics and function

Energetic redistribution in allostery to execute protein function

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