Pasteurella multocida toxin as a tool for studying Gq signal transduction

Wilson, Brenda A.; Ho, Mengfei

doi:10.1007/s10254-004-0032-6

Cited by 29 publications

(21 citation statements)

References 93 publications

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“…Cholera (33), pertussis (34), and Pasturella multocida (35) toxins are well known modulators of G protein activity. As a G q -specific inhibitor, YM-254890 should be a useful addition to the tools available to analyze diverse G protein signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Nishimura

Kitano

Takasaki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

229

317

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Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered G q -selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of α subunit of G q protein (Gα q ) by inhibiting the GDP release from Gα q . X-ray crystal structure analysis of the Gα q βγ–YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Gα q . The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each Gα subunit and an insight into the molecular mechanism of G protein activation.

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Section: Resultsmentioning

confidence: 99%

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Nishimura

Kitano

Takasaki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

229

317

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“…The antibody against G ␣ q/11 blocked PMT-induced Ca 2+ -dependent Cl -currents, whereas the antibodies against other G ␣ nor G ␤ did not. They proposed that PMT might act on GDP-bound G ␣ q/11, and convert it into an GTP-bound active form [82] ( fig. 2 ).…”

Section: P Multocida Toxin Pmtmentioning

confidence: 99%

Functions and Regulatory Mechanisms of Gq-Signaling Pathways

Mizuno

Itoh²

2009

Neurosignals

150

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Gq family members of heterotrimeric G protein activate β isoforms of phospholipase C that hydrolyzes phosphatidylinositol phosphate to diacylglycerol and inositol trisphosphate, leading to the protein kinase C activation and intracellular Ca²⁺ mobilization, respectively. To understand the functions and regulatory mechanisms of Gq-signaling pathways, we first introduce the Gαq-interacting proteins, which function as the effectors and the modulators of Gq. Next, we describe the Pasteurella multocida toxin and YM-254890, which are useful tools to investigate Gq signaling as activator and inhibitor, respectively. Finally, we discuss the physiological function of Gq in developmental brain, especially in neural progenitor cells.

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“…The primary intracellular target of PMT responsible for activation of the phospholipase C b1 (PLCb1) pathway is the free, monomeric a subunit of the G q protein (Wilson et al 1997;Zywietz et al 2001;Wilson and Ho 2004). PMT-induced stimulation of PLCb1 by Ga q leads to the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate and diacylglycerol.…”

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confidence: 99%

The C3 domain ofPasteurella multocidatoxin is the minimal domain responsible for activation of G_q‐dependent calcium and mitogenic signaling

et al. 2008

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The large 1285-amino-acid protein toxin from Pasteurella multocida (PMT) is a multifunctional singlechain polypeptide that binds to and enters eukaryotic cells and acts intracellularly to promote G q and G 12/13 protein-dependent calcium and mitogenic signal transduction. Previous studies indicated that the intracellular activity domain responsible for PMT action was located within the C-terminal 600-700 amino acids. In this study, we have exogenously expressed a series of N-and C-terminal PMT fragments directly in mammalian cells and have used the dual luciferase reporter system to assay for toxinmediated activation of calcium-calcineurin-NFAT signaling (NFAT-luciferase) and mitogenic serum response signaling (SRE-luciferase). Using this approach, we have defined the last 180 amino acids, which encompass the C3 domain in the crystal structure, as the minimum domain sufficient to activate both NFAT and SRE signaling pathways.

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Pasteurella multocida toxin as a tool for studying Gq signal transduction

Cited by 29 publications

References 93 publications

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Functions and Regulatory Mechanisms of Gq-Signaling Pathways

The C3 domain ofPasteurella multocidatoxin is the minimal domain responsible for activation of G_q‐dependent calcium and mitogenic signaling

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Pasteurella multocida toxin as a tool for studying Gq signal transduction

Cited by 29 publications

References 93 publications

Structural basis for the specific inhibition of heterotrimeric G q protein by a small molecule

Structural basis for the specific inhibition of heterotrimeric G q protein by a small molecule

Functions and Regulatory Mechanisms of Gq-Signaling Pathways

The C3 domain ofPasteurella multocidatoxin is the minimal domain responsible for activation of Gq‐dependent calcium and mitogenic signaling

Contact Info

Product

Resources

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Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

The C3 domain ofPasteurella multocidatoxin is the minimal domain responsible for activation of G_q‐dependent calcium and mitogenic signaling