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Large domain fluctuations on 50-ns timescale enable catalytic activity in phosphoglycerate kinase.

ABSTRACT: Large-scale domain motions of enzymes are often essential for their biological function. Phosphoglycerate kinase has a wide open domain structure with a hinge near the active center between the two domains. Applying neutron spin echo spectroscopy and small-angle neutron scattering we have investigated the internal domain dynamics. Structural analysis reveals that the holoprotein in solution seems to be more compact compared to the crystal structure but would not allow the functionally important phosphoryl transfer between the substrates if the protein were static. Brownian large-scale domain fluctuation dynamics on a timescale of 50 ns was revealed by neutron spin echo spectroscopy. The dynamics observed was compared to the displacement patterns of low-frequency normal modes. The displacements along the normal-mode coordinates describe our experimental results reasonably well. In particular, the domain movements facilitate a close encounter of the key residues in the active center to build the active configuration. The observed dynamics shows that the protein has the flexibility to allow fluctuations and displacements that seem to enable the function of the protein. Moreover, the presence of the substrates increases the rigidity, which is deduced from a faster dynamics with smaller amplitude.

SUBMITTER: Inoue R

PROVIDER: S-EPMC3042550 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Large domain fluctuations on 50-ns timescale enable catalytic activity in phosphoglycerate kinase.

Inoue R R Biehl R R Rosenkranz T T Fitter J J Monkenbusch M M Radulescu A A Farago B B Richter D D

Biophysical journal 20101001 7

Large-scale domain motions of enzymes are often essential for their biological function. Phosphoglycerate kinase has a wide open domain structure with a hinge near the active center between the two domains. Applying neutron spin echo spectroscopy and small-angle neutron scattering we have investigated the internal domain dynamics. Structural analysis reveals that the holoprotein in solution seems to be more compact compared to the crystal structure but would not allow the functionally important ...[more]

PMID: 20923666

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Project description:ObjectiveIdentifying neural activity biomarkers of brain disease is essential to provide objective estimates of disease burden, obtain reliable feedback regarding therapeutic efficacy, and potentially to serve as a source of control for closed-loop neuromodulation. In Parkinson's disease (PD), microelectrode recordings (MER) are routinely performed in the basal ganglia to guide electrode implantation for deep brain stimulation (DBS). While pathologically-excessive oscillatory activity has been observed and linked to PD motor dysfunction broadly, the extent to which these signals provide quantitative information about disease expression and fluctuations, particularly at short timescales, is unknown. Furthermore, the degree to which informative signal features are similar or different across patients has not been rigorously investigated. We sought to determine the extent to which motor error in PD across patients can be decoded on a rapid timescale using spectral features of neural activity.ApproachHere, we recorded neural activity from the subthalamic nucleus (STN) of subjects with PD undergoing awake DBS surgery while they performed an objective, continuous behavioral assessment that synthesized heterogenous PD motor manifestations to generate a scalar measure of motor dysfunction at short timescales. We then leveraged natural motor performance variations as a 'ground truth' to identify corresponding neurophysiological biomarkers.Main resultsSupport vector machines using multi-spectral decoding of neural signals from the STN succeeded in tracking the degree of motor impairment at short timescales (as short as one second). Spectral power across a wide range of frequencies, beyond the classic 'β' oscillations, contributed to this decoding, and multi-spectral models consistently outperformed those generated using more isolated frequency bands. While generalized decoding models derived across subjects were able to estimate motor impairment, patient-specific models typically performed better.SignificanceThese results demonstrate that quantitative information about short-timescale PD motor dysfunction is available in STN neural activity, distributed across various patient-specific spectral components, such that an individualized approach will be critical to fully harness this information for optimal disease tracking and closed-loop neuromodulation.

Dataset Information

Large domain fluctuations on 50-ns timescale enable catalytic activity in phosphoglycerate kinase.

Publications

Large domain fluctuations on 50-ns timescale enable catalytic activity in phosphoglycerate kinase.

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