Myelin Proteolipid Protein (PLP), but Not DM-20, Is an Inositol Hexakisphosphate-binding Protein

Yamaguchi, Yoshihide; Ikenaka, Kazuhiro; Niinobe, Michio; Yamada, Hitoshi; Mikoshiba, Katsuhiko

doi:10.1074/jbc.271.44.27838

Cited by 34 publications

(32 citation statements)

References 55 publications

(70 reference statements)

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“…4B). The V max values for InsP 5 and InsP 6 were each approximately 2 mol/mg/min. The affinity of the enzyme for InsP 6 (mean K m ϭ 3.3 M) was about 3-fold less than the affinity for InsP 5 (mean K m ϭ 1.2 M).…”

Section: Creation and Analysis Of A Ip6k⌬ Strain Of S Cerevisiae-wementioning

confidence: 99%

“…Materials-Nonradioactive InsP 6 and Ins(1,3,4,5,6)P 5 were purchased from Calbiochem (La Jolla, CA) and the Alexis Corporation (San Diego, CA), respectively. Stock solutions were prepared in 1 mM EDTA.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, an important goal of this study was to identify this "missing link" in inositide research: the PP-InsP 4 synthase. We now report that PP-InsP 4 in mammals is synthesized by the type 1 and type 2 forms of the InsP 6 kinase. In addition, we show that these enzymes can further phosphorylate PP-InsP 4 , thereby forming a hitherto unknown inositol polyphosphate.…”

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confidence: 99%

“…Other proteins that participate in intracellular trafficking can bind PP-InsP 5 very tightly, including coatomer (3,4) and AP2 (5). The high affinity with which PP-InsP 5 binds to myelin proteolipid protein may be important for the vesicular delivery of the latter to the myelin sheath (6). Prior experiments with intact cells have shown that Ins(1,3,4,5,6)P 5 and InsP 6 serve as metabolic stockpiles for the formation of the diphosphorylated inositol polyphosphates (7,8).…”

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The Inositol Hexakisphosphate Kinase Family

Saiardi¹,

Caffrey²,

Snyder³

et al. 2000

Journal of Biological Chemistry

168

123

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Saiardi et al. (Saiardi, A., Erdjument-Bromage, H., Snowman, A., Tempst, P., and Snyder, S. H. (1999) Curr. Biol. 9, 1323-1326) previously described the cloning of a kinase from yeast and two kinases from mammals (types 1 and 2), which phosphorylate inositol hexakisphosphate (InsP 6 ) to diphosphoinositol pentakisphosphate, a "high energy" candidate regulator of cellular trafficking. We have now studied the significance of InsP 6 kinase activity in Saccharomyces cerevisiae by disrupting the kinase gene. These ip6k⌬ cells grew more slowly, their levels of diphosphoinositol polyphosphates were 60 -80% lower than wild-type cells, and the cells contained abnormally small and fragmented vacuoles. Novel activities of the mammalian and yeast InsP 6 kinases were identified; inositol pentakisphosphate (InsP 5 ) was phosphorylated to diphosphoinositol tetrakisphosphate (PP-InsP 4 ), which was further metabolized to a novel compound, tentatively identified as bisdiphosphoinositol trisphosphate. The latter is a new substrate for human diphosphoinositol polyphosphate phosphohydrolase. Kinetic parameters for the mammalian type 1 kinase indicate that InsP 5 (K m ‫؍‬ 1.2 M) and InsP 6 (K m ‫؍‬ 6.7 M) compete for phosphorylation in vivo. This is the first time a PP-InsP 4 synthase has been identified. The mammalian type 2 kinase and the yeast kinase are more specialized for the phosphorylation of InsP 6 . Synthesis of the diphosphorylated inositol phosphates is thus revealed to be more complex and interdependent than previously envisaged.The very dynamic turnover of the "high energy" diphospho- For example, PP-InsP 5 represents the most potent known inhibitor of AP180-mediated assembly of clathrin cages, a key step in the endocytic retrieval of discharged synaptosomal vesicles (2). Other proteins that participate in intracellular trafficking can bind PP-InsP 5 very tightly, including coatomer (3, 4) and AP2 (5). The high affinity with which PP-InsP 5 binds to myelin proteolipid protein may be important for the vesicular delivery of the latter to the myelin sheath (6).Prior experiments with intact cells have shown that Ins(1,3,4,5,6)P 5 and InsP 6 serve as metabolic stockpiles for the formation of the diphosphorylated inositol polyphosphates (7,8). InsP 6 is the precursor for PP-InsP 5 , which is further phosphorylated to [PP] 2 -InsP 4 (5, 7-10). These reactions appear to take place within a metabolic pool that is separate from that in which Ins(1,3,4,5,6)P 5 and PP-InsP 4 are interconverted (7). Thus, there are two metabolic pools of inositol diphosphates that are turned over in parallel cycles.There are increasing efforts to characterize the activities of the enzymes that regulate the turnover of PP-InsP 4 , PP-InsP 5 , and [PP] 2 -InsP 4 . Several phosphatases (diphosphoinositol polyphosphate phosphohydrolases) that hydrolyze these compounds have been described (11,12). Two forms of InsP 6 kinase (types 1 and 2), derived from distinct genes, have been cloned from mammals (13,14). At least in mammals, the further phosphorylati...

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Section: Creation and Analysis Of A Ip6k⌬ Strain Of S Cerevisiae-wementioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The Inositol Hexakisphosphate Kinase Family

Saiardi¹,

Caffrey²,

Snyder³

et al. 2000

Journal of Biological Chemistry

168

123

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“…However, there are few accompanying demonstrations that ligand binding alters the function of the target protein. For example, there is no indication as to the possible physiological consequences of InsP 6 binding tightly to either vinculin, a component of platelet cytoskeleton (141) or to myelin proteolipid protein, which participates in myelin deposition (142) or to coatomer, which regulates vesicle traffic between the ER and the Golgi (143,144).…”

Section: Inspmentioning

confidence: 99%

The Structural and Functional Versatility of Inositol Phosphates

Caffrey

Safrany

Yang

et al. 1998

ACS Symposium Series

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This review presents a summary of our current knowledge of inositol phosphate turnover in animal cells. In the Figure 1, the various metabolic reactions are sub-divided into several distinct groups; each of these is discussed in turn in this review, in an effort to illustrate the functional versatility of these polyphosphates.The Ins(l,4,5)P 3 / Ins(l,3,4,5)P 4 cycleThe discovery of inositol phosphate-mediated cellular Ca 2+ mobilization was a pivotal development in the field of signal transduction (/), but this breakthrough also owes much to the persistence of some other workers who had the foresight to develop and promote the idea of receptor-activated inositide signaling. It was the Hokins who first discovered that muscarinic agonists accelerate the turnover of Ptdlns in tissue slices from brain and pancreas (2). It was unfortunate that their dedication to characterizing this effect over the following 20 years did not lead them to ascribe its biological function. Indeed, there was little general interest in this so-called "phosphoinositide effect", until Michell (3) proposed that it might drive receptor-dependent Ca 2+ influx into the cell. Later, Michell and his colleagues showed mat an accelerated PtdIns(4,5)P 2 turnover immediately followed receptor-occupation by Ca 2+ -mobilizing hormones (4,5). The modem era of inositide research was now bom: Berridge (6) recognized that the Ins(l,4,5)P 3 formed by hydrolysis of PtdIns(4,5)P 2 was a candidate intracellular signal, and so it was discovered that Ins(l,4,5)/\ released Ca 2+ from endoplasmic reticulum (ER) (7). This intracellular release of Ca was found to be co-ordinated with an increase in the rate of Ca 2+ influx into the cell (7) -which finally confirmed the essence of the original idea (3) that inositol lipid turnover regulated Ca 2+ entry.Ins(l,4,5)P 3 -induced Ca 2+ release mediates an abundance of cellular responses as diverse as fertilization, cell growth and differentiation, neuronal signaling, secretion, and phototransduction. The distinct signaling requirements of individual cells are served by cell-and agonist-specific spatiotemporal patterns of Ca 2+ signaling. These arise not just from the binding of Ins(l,4,5)P 3 to its receptor, but also by modulation of this ligand/protein interaction by both cytosolic and ER-luminal Ca 2+ , and there is also input from the process of Ca 2+ entry, and Ins(l,4,5)P 3 metabolism (8). There is also regulatory diversity between the three major forms of the Ins(l,4,5)P 3 receptors that are currently recognized (see reference 9 for a review).

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