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Dynamic Coupling and Allosteric Networks in the ? Subunit of Heterotrimeric G Proteins.

ABSTRACT: G protein ? subunits cycle between active and inactive conformations to regulate a multitude of intracellular signaling cascades. Important structural transitions occurring during this cycle have been characterized from extensive crystallographic studies. However, the link between observed conformations and the allosteric regulation of binding events at distal sites critical for signaling through G proteins remain unclear. Here we describe molecular dynamics simulations, bioinformatics analysis, and experimental mutagenesis that identifies residues involved in mediating the allosteric coupling of receptor, nucleotide, and helical domain interfaces of G?i. Most notably, we predict and characterize novel allosteric decoupling mutants, which display enhanced helical domain opening, increased rates of nucleotide exchange, and constitutive activity in the absence of receptor activation. Collectively, our results provide a framework for explaining how binding events and mutations can alter internal dynamic couplings critical for G protein function.

SUBMITTER: Yao XQ

PROVIDER: S-EPMC4813496 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Dynamic Coupling and Allosteric Networks in the α Subunit of Heterotrimeric G Proteins.

Yao Xin-Qiu XQ Malik Rabia U RU Griggs Nicholas W NW Skjærven Lars L Traynor John R JR Sivaramakrishnan Sivaraj S Grant Barry J BJ

The Journal of biological chemistry 20151224 9

G protein α subunits cycle between active and inactive conformations to regulate a multitude of intracellular signaling cascades. Important structural transitions occurring during this cycle have been characterized from extensive crystallographic studies. However, the link between observed conformations and the allosteric regulation of binding events at distal sites critical for signaling through G proteins remain unclear. Here we describe molecular dynamics simulations, bioinformatics analysis, ...[more]

PMID: 26703464

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Project description:Oscillatory behavior of mitochondrial inner membrane potential (??m) is commonly observed in cells subjected to oxidative or metabolic stress. In cardiac myocytes, the activation of inner membrane pores by reactive oxygen species (ROS) is a major factor mediating intermitochondrial coupling, and ROS-induced ROS release has been shown to underlie propagated waves of ??m depolarization as well as synchronized limit cycle oscillations of ??m in the network. The functional impact of ??m instability on cardiac electrophysiology, Ca(2+) handling, and even cell survival, is strongly affected by the extent of such intermitochondrial coupling. Here, we employ a recently developed wavelet-based analytical approach to examine how different substrates affect mitochondrial coupling in cardiac cells, and we also determine the oscillatory coupling properties of mitochondria in ventricular cells in intact perfused hearts. The results show that the frequency of ??m oscillations varies inversely with the size of the oscillating mitochondrial cluster, and depends on the strength of local intermitochondrial coupling. Time-varying coupling constants could be quantitatively determined by applying a stochastic phase model based on extension of the well-known Kuramoto model for networks of coupled oscillators. Cluster size-frequency relationships varied with different substrates, as did mitochondrial coupling constants, which were significantly larger for glucose (7.78 × 10(-2) ± 0.98 × 10(-2) s(-1)) and pyruvate (7.49 × 10(-2) ± 1.65 × 10(-2) s(-1)) than lactate (4.83 × 10(-2) ± 1.25 × 10(-2) s(-1)) or ?-hydroxybutyrate (4.11 × 10(-2) ± 0.62 × 10(-2) s(-1)). The findings indicate that mitochondrial spatiotemporal coupling and oscillatory behavior is influenced by substrate selection, perhaps through differing effects on ROS/redox balance. In particular, glucose-perfusion generates strong intermitochondrial coupling and temporal oscillatory stability. Pathological changes in specific catabolic pathways, which are known to occur during the progression of cardiovascular disease, could therefore contribute to altered sensitivity of the mitochondrial network to oxidative stress and emergent ??m instability, ultimately scaling to produce organ level dysfunction.

Dataset Information

Dynamic Coupling and Allosteric Networks in the ? Subunit of Heterotrimeric G Proteins.

Publications

Dynamic Coupling and Allosteric Networks in the α Subunit of Heterotrimeric G Proteins.

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