Structural insight into inositol pyrophosphate turnover

Shears, Stephen B.; Weaver, Jeremy D.; Wang, Huanchen

doi:10.1016/j.jbior.2012.10.002

Cited by 18 publications

(20 citation statements)

References 69 publications

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“…Intracellular 5-IP 7 concentrations are in the low micromolar range and show extremely rapid and dynamic turnover (9,(22)(23)(24)(25), consistent with our conclusion that 5-IP 7 functions as a molecular switch for synaptic exocytosis. We speculate that IP6K1 and its product 5-IP 7 may exert multiple modes of regulation at different levels.…”

Section: Discussionsupporting

confidence: 88%

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Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Lee

Kyung

et al. 2016

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

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Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6. Synaptotagmin 1 (Syt1), a Ca2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7. Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6. In addition, 5-IP7–dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca2+ levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca2+. These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.

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Section: Discussionsupporting

confidence: 88%

“…Given the unique chemical configuration of the IP 7 structure, the dynamic turnover of cellular IP 7 levels (9,(22)(23)(24)(25), and implications…”

mentioning

confidence: 99%

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Lee

Kyung

et al. 2016

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

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“…2.7.1.158), inositol pentakisphosphate kinase; IP6K (E.C.2.7.4.21), inositol hexakisphosphate kinase, PPIP5K (E.C.2.7.4.24), diphosphoinositol pentakisphophate kinase. This figure is adapted from (Shears et al, 2013). For the brave-hearted who wish to gain insight into the unassailable logic behind the universal numbering system for the six carbon atoms of Ins, start here: (Nomenclature Committee of the International Union of Biochemistry., 1989).…”

Section: Figmentioning

confidence: 99%

Inositol pyrophosphates: Why so many phosphates?

Shears

2015

Advances in Biological Regulation

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115

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The inositol pyrophosphates (PP-InsPs) are a specialized group of “energetic” signaling molecules found in yeasts, plants and animals. PP-InsPs boast the most crowded three dimensional phosphate arrays found in Nature; multiple phosphates and diphosphates are crammed around the six-carbon, inositol ring. Yet, phosphate esters are also a major energy currency in cells. So the synthesis of PP-InsPs, and the maintenance of their levels in the face of a high rate of ongoing turnover, all requires significant bioenergetic input. What are the particular properties of PP-InsPs that repay this investment of cellular energy? Potential answers to that question are discussed here, against the backdrop of a recent hypothesis that signaling by PP-InsPs is evolutionarily ancient. The latter idea is extended herein, with the proposal that the primordial origins of PP-InsPs is reflected in the apparent lack of isomeric specificity of certain of their actions. Nevertheless, there are other aspects of signaling by these polyphosphates that are more selective for a particular PP-InsP isomer. Consideration of the nature of both specific and non-specific effects of PP-InsPs can help rationalize why such molecules possess so many phosphates.

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“…InsP7 has been implicated in a variety of cellular functions such as vesicular trafficking, apoptosis, endocytosis, DNA repair/recombination, and maintenance of telomere length . InsP7 arises from pyrophosphorylation of InsP6, the most abundant inositol phosphate in mammalian cells . The enzymes that catalyze the synthesis of InsP7 comprise a family of InsP6 kinases (InsP6K) including InsP6K1, InsP6K2, and InsP6K3 (Fig ).…”

Section: Regulation Of Ptdins(345)p3 Signaling By Inositol Phosphatesmentioning

confidence: 99%

Molecular control of PtdIns(3,4,5)P3 signaling in neutrophils

Luo

Mondal

2015

EMBO Reports

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Neutrophils play critical roles in innate immunity and host defense. However, excessive neutrophil accumulation or hyperresponsiveness of neutrophils can be detrimental to the host system. Thus, the response of neutrophils to inflammatory stimuli needs to be tightly controlled. Many cellular processes in neutrophils are mediated by localized formation of an inositol phospholipid, phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3), at the plasma membrane. The PtdIns(3,4,5)P3 signaling pathway is negatively regulated by lipid phosphatases and inositol phosphates, which consequently play a critical role in controlling neutrophil function and would be expected to act as ideal therapeutic targets for enhancing or suppressing innate immune responses. Here, we comprehensively review current understanding about the action of lipid phosphatases and inositol phosphates in the control of neutrophil function in infection and inflammation.

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Structural insight into inositol pyrophosphate turnover

Cited by 18 publications

References 69 publications

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

Inositol pyrophosphates: Why so many phosphates?

Molecular control of PtdIns(3,4,5)P3 signaling in neutrophils

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