Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels

Signature de l'adaptation des protéines à l'environnement des fonds marins chauds: le cas du Facteur d'Initiation 6 étudié par simulation moléculaire et diffusion de neutrons.

The protein Initiation Factor 6 (IF6) takes part in the protein synthesis regulation of several organisms. It was also found in archeaebacteria such as Methanoccoccus Jannascii which lives in deep-seas near hydrothermal vents where temperature reaches 80°C and pressure is between 250bar and 500bar. The aim of this work was to study for the first time dynamical and structural properties of IF6 produced by M.Jannaschii and comparing them with those of the IF6 homologue present in Saccharomyces cerevisiae which lives at "normal" environmental conditions (27°C and 1bar). Molecular simulation gave here new insights into the adaptation of these two proteins to their respective physiological conditions and showed that the latter induced similar dynamical and structural properties: in their respective "natural" conditions, IF6s show very similar structural fluctuations and the characteristic relaxation times which define their dynamical properties shows similar changes when comparing unfavorable conditions to physiological ones. The creation of these corresponding states between the two homologues has been interpreted by the fractional Brownian dynamics model and by a novel method for the characterization of protein secondary structures. The latter is presented here in detail together with some examples of other applications. Experimental data obtained from quasi-elastic neutron scattering seemed to support the results obtained by molecular simulations.Le Facteur d'Initiation 6 (IF6) est une protéine qui participe, dans plusieurs organismes, à la régulation de la synthèse des autres protéines. Elle a été trouvée aussi dans l'archaebactérie Methanoccoccus Jannascii qui vit au fond de la mer, près des cheminées hydrothermales, où la température atteint 80°C et la pression hydrostatique est entre 250 et 500bar. L'objectif de ce travail a été celui d'étudier pour la première fois les propriétés dynamiques et structurales de la IF6 issue du M.Jannaschii en comparaison avec celles de son homologue présent dans le Saccharomyces cerevisiae qui vit dans des conditions environnementales "normales" (27°C et 1bar). La simulation moléculaire nous a permis de montrer que l'adaptation de ces deux protéines aux conditions physiologiques induit des propriétés dynamiques et structurales similaires: dans leur conditions "naturelles" respectives, les deux protéines montrent des fluctuations structurales très similaires et les temps caractéristiques qui identifient leur propriétés dynamiques subissent les mêmes changements dans la transition d'une condition défavorable vers la condition physiologique. Cette création d' "états correspondants" entre les deux protéines a été étudiée par le modèle de dynamique Brownienne fractionnaire et par une nouvelle méthode pour la caractérisation des structures secondaires des protéines. Cette dernière est présentée en détail avec des brefs exemples d'autres applications. Les données préliminaires obtenues par diffusion de neutrons semblent confirmer les résultats issues des simulations moléculaires

Signature of protein adaptation to warm deep sea environments (the case of Initiation Factor 6 studied by molecular simulation and neutron scattering)

Le Facteur d Initiation 6 (IF6) est une protéine qui participe, dans plusieurs organismes, à larégulation de la synthèse des autres protéines. Elle a été trouvée aussi dans l archaebactérie Methanoccoccus Jannascii qui vit au fond de la mer, près des cheminées hydrothermales, où la température atteint 80 C et la pression hydrostatique est entre 250 et 500bar. L objectif de ce travail a été celui d étudier pour la première fois les propriétés dynamiques et structurales de la IF6 issue du M.Jannaschii en comparaison avec celles de son homologue présent dans le Saccaromyces cerevisiae qui vit dans des conditions environnementales "normales" (27 C et 1bar). La simulation moléculaire nous a permit de montrer que l adaptation de ces deux protéines aux conditions physiologiques induit des propriétés dynamiques et structurales similaires : dans leur conditions "naturelles" respectives les deux protéines montrent des fluctuations structurales très similaires et les temps caractéristiques qui identifient leur propriétés dynamiques subissent les mêmes changements dans la transition d une condition défavorable vers la condition physiologique. Cette création d "états correspondants" entre les deux protéines a été étudiée par le modèle de dy- namique Brownienne fractionnaire et par une nouvelle méthode pour la caractérisation des structures secondaires des protéines. Cette dernière est présentée en détail avec des brefs exemples d autres applications. Les données préliminaires obtenues par diffusion de neutrons semblent confirmer les résultats issues des simulations moléculairesPARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Toward the characterization of fractional stochastic processes underlying methyl dynamics in proteins

International audienceIn this article, we investigate the multiple scale structure of methyl side chain dynamics in proteins. We show that the orientational correlation functions of CH3 methyl groups are well described by a fractional Brownian dynamics model. Typical angular correlation functions involved in NMR relaxation were computed from MD simulations performed on two different proteins. These correlation functions were shown to be very well fitted by a fractional Ornstein-Uhlenbeck process in the presence of a effective local potentials at the C-H and C-C methyl bonds. In addition, our analysis highlights the presence of the asymptotic power law decay of the waiting time probability density of the stochastic process involved, thereby illustrating the connection between approaches based on fractional diffusion equations and the continuous time random walk (CTRW)

ScrewFit: Combining localization and description of protein secondary structure

International audienceA new application of the ScrewFit algorithm [Kneller & Calligari (2006), Acta Cryst. D62, 302-311] is presented which adds the detection of protein secondary-structure elements to their detailed geometrical description in terms of a curve with intrinsic torsion. The extension is based on confidence and persistence criteria for the ScrewFit parameters which are established by analyzing the structural fluctuations of standard motifs in the SCOP fold classes. The agreement with the widely used DSSP method is comparable with the general consensus among other methods in the literature. This combination of secondary-structure detection and analysis is illustrated for the enzyme adenylate kinase

Efficient characterization of protein secondary structure in terms of screw motions

A simple and efficient method is presented to describe the secondary structure of proteins in terms of orientational distances between consecutive peptide planes and local helix parameters. The method uses quaternion-based superposition fits of the protein peptide planes in conjunction with Chasles' theorem, which states that any rigid-body displacement can be described by a screw motion. The helix parameters are derived from the best superposition of consecutive peptide planes and the ;worst' fit is used to define the orientational distance. Applications are shown for standard secondary-structure motifs of peptide chains for several proteins belonging to different fold classes and for a description of structural changes in lysozyme under hydrostatic pressure. In the latter case, published reference data obtained by X-ray crystallography and by structural NMR measurements are used

Communication: A minimal model for the diffusion-relaxation backbone dynamics of proteins

International audienceWe present a model for the local diffusion-relaxation dynamics of the C(α)-atoms in proteins describing both the diffusive short-time dynamics and the asymptotic long-time relaxation of the position autocorrelation functions. The relaxation rate spectra of the latter are represented by shifted gamma distributions, where the standard gamma distribution describes anomalous slow relaxation in macromolecular systems of infinite size and the shift accounts for a smallest local relaxation rate in macromolecules of finite size. The resulting autocorrelation functions are analytic for any time t ≥ 0. Using results from a molecular dynamics simulation of lysozyme, we demonstrate that the model fits the position autocorrelation functions of the C(α)-atoms exceptionally well and reveals moreover a strong correlation between the residue's solvent-accessible surface and the fitted model parameters

Toward the Characterization of Fractional Stochastic Processes Underlying Methyl Dynamics in Proteins

In this article, we investigate the multiple-scale structure of methyl side chain dynamics in proteins. We show that the orientational correlation functions of CH₃ methyl groups are well described by a fractional Brownian dynamics model. Typical angular correlation functions involved in NMR relaxation were computed from MD simulations performed on two different proteins. These correlation functions were shown to be very well fitted by a fractional Ornstein–Uhlenbeck process in the presence of effective local potentials at the C–H and C–C methyl bonds. In addition, our analysis highlights the presence of the asymptotic power law decay of the waiting time probability density of the stochastic process involved, thereby illustrating the connection between approaches based on fractional diffusion equations and the continuous time random walk

Molecular investigation of SARS-CoV-2 proteins and their interactions with antiviral drugs

A new Coronavirus strain, named SARS-CoV-2, suddenly emerged in early December 2019. SARS-CoV-2 resulted in being dramatically infectious, with thousands of people infected. In this scenario, and without effective vaccines available, the importance of an immediate tool to support patients and against viral diffusion becomes evident. In this study, we exploit the molecular docking approach to analyze the affinity between different viral proteins and several inhibitors, originally developed for other viral infections. Our data show that, in some cases, a relevant binding can be detected. These findings support the hypothesis to develop new antiviral agents against COVID-19, on the basis of already established therapies