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Exploring allosteric coupling in the alpha-subunit of heterotrimeric G proteins using evolutionary and ensemble-based approaches.

ABSTRACT: BACKGROUND: Allosteric coupling, which can be defined as propagation of a perturbation at one region of the protein molecule (such as ligand binding) to distant sites in the same molecule, constitutes the most general mechanism of regulation of protein function. However, unlike molecular details of ligand binding, structural elements involved in allosteric effects are difficult to diagnose. Here, we identified allosteric linkages in the alpha-subunits of heterotrimeric G proteins, which were evolved to transmit membrane receptor signals by allosteric mechanisms, by using two different approaches that utilize fundamentally different and independent information. RESULTS: We analyzed: 1) correlated mutations in the family of G protein alpha-subunits, and 2) cooperativity of the native state ensemble of the Galphai1 or transducin. The combination of these approaches not only recovered already-known details such as the switch regions that change conformation upon nucleotide exchange, and those regions that are involved in receptor, effector or Gbetagamma interactions (indicating that the predictions of the analyses can be viewed with a measure of confidence), but also predicted new sites that are potentially involved in allosteric communication in the Galpha protein. A summary of the new sites found in the present analysis, which were not apparent in crystallographic data, is given along with known functional and structural information. Implications of the results are discussed. CONCLUSION: A set of residues and/or structural elements that are potentially involved in allosteric communication in Galpha is presented. This information can be used as a guide to structural, spectroscopic, mutational, and theoretical studies on the allosteric network in Galpha proteins, which will provide a better understanding of G protein-mediated signal transduction.

SUBMITTER: Sayar K

PROVIDER: S-EPMC2422842 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Exploring allosteric coupling in the alpha-subunit of heterotrimeric G proteins using evolutionary and ensemble-based approaches.

Sayar Kemal K Uğur Ozlem O Liu Tong T Hilser Vincent J VJ Onaran Ongun O

BMC structural biology 20080502

<h4>Background</h4>Allosteric coupling, which can be defined as propagation of a perturbation at one region of the protein molecule (such as ligand binding) to distant sites in the same molecule, constitutes the most general mechanism of regulation of protein function. However, unlike molecular details of ligand binding, structural elements involved in allosteric effects are difficult to diagnose. Here, we identified allosteric linkages in the alpha-subunits of heterotrimeric G proteins, which w ...[more]

PMID: 18454845

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Project description:BackgroundHeterotrimeric G proteins are fundamental signaling proteins composed of three subunits, Gα and a Gβγ dimer. The role of Gα as a molecular switch is critical for transmitting and amplifying intracellular signaling cascades initiated by an activated G protein Coupled Receptor (GPCR). Despite their biochemical and therapeutic importance, the study of G protein evolution has been limited to the scope of a few model organisms. Furthermore, of the five primary Gα subfamilies, the underlying gene structure of only two families has been thoroughly investigated outside of Mammalia evolution. Therefore our understanding of Gα emergence and evolution across phylogeny remains incomplete.ResultsWe have computationally identified the presence and absence of every Gα gene (GNA-) across all major branches of Deuterostomia and evaluated the conservation of the underlying exon-intron structures across these phylogenetic groups. We provide evidence of mutually exclusive exon inclusion through alternative splicing in specific lineages. Variations of splice site conservation and isoforms were found for several paralogs which coincide with conserved, putative motifs of DNA-/RNA-binding proteins. In addition to our curated gene annotations, within Primates, we identified 15 retrotranspositions, many of which have undergone pseudogenization. Most importantly, we find numerous deviations from previous findings regarding the presence and absence of individual GNA- genes, nuanced differences in phyla-specific gene copy numbers, novel paralog duplications and subsequent intron gain and loss events.ConclusionsOur curated annotations allow us to draw more accurate inferences regarding the emergence of all Gα family members across Metazoa and to present a new, updated theory of Gα evolution. Leveraging this, our results are critical for gaining new insights into the co-evolution of the Gα subunit and its many protein binding partners, especially therapeutically relevant G protein - GPCR signaling pathways which radiated in Vertebrata evolution.

Dataset Information

Exploring allosteric coupling in the alpha-subunit of heterotrimeric G proteins using evolutionary and ensemble-based approaches.

Publications

Exploring allosteric coupling in the alpha-subunit of heterotrimeric G proteins using evolutionary and ensemble-based approaches.

Similar Datasets

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