Dataset Information

?C helix as a switch in the conformational transition of Src/CDK-like kinase domains.

ABSTRACT: One mechanism of regulating the catalytic activity of protein kinases is through conformational transitions. Despite great diversity in the structural changes involved in the transitions, a certain set of changes within the kinase domain (KD) has been observed for many kinases including Src and CDK2. We investigated this conformational transition computationally to identify the topological features that are energetically critical to the transition. Results from both molecular dynamics sampling and transition path optimization highlight the displacement of the ?C helix as the major energy barrier, mediating the switch of the KD between the active and down-regulated states. The critical role of the ?C helix is noteworthy by providing a rationale for a number of activation and deactivation mechanisms known to occur in cells. We find that kinases with the ?C helix displacement exist throughout the kinome, suggesting that this feature may have emerged early in evolution.

SUBMITTER: Huang H

PROVIDER: S-EPMC3630996 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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αC helix as a switch in the conformational transition of Src/CDK-like kinase domains.

Huang He H Zhao Ruijun R Dickson Bradley M BM Skeel Robert D RD Post Carol Beth CB

The journal of physical chemistry. B 20120405 15

One mechanism of regulating the catalytic activity of protein kinases is through conformational transitions. Despite great diversity in the structural changes involved in the transitions, a certain set of changes within the kinase domain (KD) has been observed for many kinases including Src and CDK2. We investigated this conformational transition computationally to identify the topological features that are energetically critical to the transition. Results from both molecular dynamics sampling a ...[more]

PMID: 22448785

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Project description:We report a conformational switch between two distinct intrinsically disordered subensembles within the active site of a transcription factor. This switch highlights an evolutionary benefit conferred by the high plasticity of intrinsically disordered domains, namely, their potential to dynamically sample a heterogeneous conformational space housing multiple states with tailored properties. We focus on proto-oncogenic basic-helix-loop-helix (bHLH)-type transcription factors, as these play key roles in cell regulation and function. Despite intense research efforts, the understanding of structure-function relations of these transcription factors remains incomplete as they feature intrinsically disordered DNA-interaction domains that are difficult to characterize, theoretically as well as experimentally. Here we characterize the structural dynamics of the intrinsically disordered region DNA-binding site of the vital MYC-associated transcription factor X (MAX). Integrating nuclear magnetic resonance (NMR) measurements, molecular dynamics (MD) simulations, and electron paramagnetic resonance (EPR) measurements, we show that, in the absence of DNA, the binding site of the free MAX2 homodimer samples two intrinsically disordered conformational subensembles. These feature distinct structural properties: one subensemble consists of a set of highly flexible and spatially extended conformers, while the second features a set of "hinged" conformations. In this latter ensemble, the disordered N-terminal tails of MAX2 fold back along the dimer, forming transient long-range contacts with the HLH-region and thereby exposing the DNA binding site to the solvent. The features of these divergent substates suggest two mechanisms by which protein conformational dynamics in MAX2 might modulate DNA-complex formation: by enhanced initial recruitment of free DNA ligands, as a result of the wider conformational space sampled by the extended ensemble, and by direct exposure of the binding site and the corresponding strong electrostatic attractions presented while in the hinged conformations.

Dataset Information

?C helix as a switch in the conformational transition of Src/CDK-like kinase domains.

Publications

αC helix as a switch in the conformational transition of Src/CDK-like kinase domains.

Similar Datasets

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