Karttunen Sarah, Duffield Michael, Scrimgeour Nathan R, Squires Lauren, Lim Wai Li, Dallas Mark L, Scragg Jason L, Chicher Johana, Dave Keyur A, Whitelaw Murray L, Peers Chris, Gorman Jeffrey J, Gleadle Jonathan M, Rychkov Grigori Y, Peet Daniel J
Oxygen-dependent hydroxylation by FIH regulates the TRPV3 ion channel. Journal Article
In: Journal of cell science, vol. 128, no. 2, pp. 225–231, 2015, ISSN: 1477-9137 0021-9533, (Place: England).
Abstract | Links | BibTeX | Tags: alpha Subunit/genetics/*metabolism, Amino Acid Sequence, Ankyrin Repeat/genetics, Cell Hypoxia/*genetics, FIH, HEK293 Cells, Humans, Hydroxylation, Hydroxylation/genetics, Hypoxia, Hypoxia-Inducible Factor 1, Mixed Function Oxygenases/antagonists & inhibitors/genetics/*metabolism, Mutation, Oxygen/metabolism, PPSE, Protein Binding, Repressor Proteins/antagonists & inhibitors/genetics/*metabolism, TRPV Cation Channels/genetics/*metabolism, TRPV3
@article{karttunen_oxygen-dependent_2015,
title = {Oxygen-dependent hydroxylation by FIH regulates the TRPV3 ion channel.},
author = {Sarah Karttunen and Michael Duffield and Nathan R Scrimgeour and Lauren Squires and Wai Li Lim and Mark L Dallas and Jason L Scragg and Johana Chicher and Keyur A Dave and Murray L Whitelaw and Chris Peers and Jeffrey J Gorman and Jonathan M Gleadle and Grigori Y Rychkov and Daniel J Peet},
doi = {10.1242/jcs.158451},
issn = {1477-9137 0021-9533},
year = {2015},
date = {2015-01-01},
journal = {Journal of cell science},
volume = {128},
number = {2},
pages = {225--231},
abstract = {Factor inhibiting HIF (FIH, also known as HIF1AN) is an oxygen-dependent asparaginyl hydroxylase that regulates the hypoxia-inducible factors (HIFs). Several proteins containing ankyrin repeat domains (ARDs) have been characterised as substrates of FIH, although there is little evidence for a functional consequence of hydroxylation on these substrates. This study demonstrates that the transient receptor potential vanilloid 3 (TRPV3) channel is hydroxylated by FIH on asparagine 242 within the cytoplasmic ARD. Hypoxia, FIH inhibitors and mutation of asparagine 242 all potentiated TRPV3-mediated current, without altering TRPV3 protein levels, indicating that oxygen-dependent hydroxylation inhibits TRPV3 activity. This novel mechanism of channel regulation by oxygen-dependent asparaginyl hydroxylation is likely to extend to other ion channels.},
note = {Place: England},
keywords = {alpha Subunit/genetics/*metabolism, Amino Acid Sequence, Ankyrin Repeat/genetics, Cell Hypoxia/*genetics, FIH, HEK293 Cells, Humans, Hydroxylation, Hydroxylation/genetics, Hypoxia, Hypoxia-Inducible Factor 1, Mixed Function Oxygenases/antagonists & inhibitors/genetics/*metabolism, Mutation, Oxygen/metabolism, PPSE, Protein Binding, Repressor Proteins/antagonists & inhibitors/genetics/*metabolism, TRPV Cation Channels/genetics/*metabolism, TRPV3},
pubstate = {published},
tppubtype = {article}
}
Zhang Na, Fu Zhenxing, Linke Sarah, Chicher Johana, Gorman Jeffrey J, Visk DeeAnn, Haddad Gabriel G, Poellinger Lorenz, Peet Daniel J, Powell Frank, Johnson Randall S
The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Journal Article
In: Cell metabolism, vol. 11, no. 5, pp. 364–378, 2010, ISSN: 1932-7420 1550-4131 1550-4131.
Abstract | Links | BibTeX | Tags: alpha Subunit/*antagonists & inhibitors/genetics, Animals, Asparagine/genetics/metabolism, Dietary Fats/pharmacology, Fatty Liver/etiology, Glucose/metabolism, Hyperventilation/etiology, Hypoxia-Inducible Factor 1, Insulin/metabolism, Knockout, Lipid Metabolism, Mice, Mixed Function Oxygenases/deficiency/genetics/*metabolism, PPSE, Transcriptional Activation, Weight Gain
@article{zhang_asparaginyl_2010,
title = {The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.},
author = {Na Zhang and Zhenxing Fu and Sarah Linke and Johana Chicher and Jeffrey J Gorman and DeeAnn Visk and Gabriel G Haddad and Lorenz Poellinger and Daniel J Peet and Frank Powell and Randall S Johnson},
doi = {10.1016/j.cmet.2010.03.001},
issn = {1932-7420 1550-4131 1550-4131},
year = {2010},
date = {2010-01-01},
journal = {Cell metabolism},
volume = {11},
number = {5},
pages = {364--378},
abstract = {Factor inhibiting HIF-1alpha (FIH) is an asparaginyl hydroxylase. Hydroxylation of HIF-alpha proteins by FIH blocks association of HIFs with the transcriptional coactivators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, and improved glucose and lipid homeostasis and are resistant to high-fat-diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, and enhanced insulin sensitivity and are also protected against high-fat-diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism.},
keywords = {alpha Subunit/*antagonists & inhibitors/genetics, Animals, Asparagine/genetics/metabolism, Dietary Fats/pharmacology, Fatty Liver/etiology, Glucose/metabolism, Hyperventilation/etiology, Hypoxia-Inducible Factor 1, Insulin/metabolism, Knockout, Lipid Metabolism, Mice, Mixed Function Oxygenases/deficiency/genetics/*metabolism, PPSE, Transcriptional Activation, Weight Gain},
pubstate = {published},
tppubtype = {article}
}
Wilkins Sarah E, Hyvärinen Jaana, Chicher Johana, Gorman Jeffrey J, Peet Daniel J, Bilton Rebecca L, Koivunen Peppi
Differences in hydroxylation and binding of Notch and HIF-1alpha demonstrate substrate selectivity for factor inhibiting HIF-1 (FIH-1). Journal Article
In: The international journal of biochemistry & cell biology, vol. 41, no. 7, pp. 1563–1571, 2009, ISSN: 1878-5875 1357-2725, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: alpha Subunit/*metabolism, Amino Acid Sequence, Animals, Asparagine/metabolism, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, Kinetics, Mice, Mixed Function Oxygenases, Molecular Sequence Data, Notch/chemistry/*metabolism, Oxygen/metabolism, Peptides/chemistry/metabolism, PPSE, Protein Binding, Receptors, Recombinant Proteins/metabolism, Repressor Proteins/*metabolism, Substrate Specificity
@article{wilkins_differences_2009,
title = {Differences in hydroxylation and binding of Notch and HIF-1alpha demonstrate substrate selectivity for factor inhibiting HIF-1 (FIH-1).},
author = {Sarah E Wilkins and Jaana Hyvärinen and Johana Chicher and Jeffrey J Gorman and Daniel J Peet and Rebecca L Bilton and Peppi Koivunen},
doi = {10.1016/j.biocel.2009.01.005},
issn = {1878-5875 1357-2725},
year = {2009},
date = {2009-01-01},
journal = {The international journal of biochemistry & cell biology},
volume = {41},
number = {7},
pages = {1563--1571},
abstract = {FIH-1, factor inhibiting hypoxia-inducible factor-1 (HIF-1), regulates oxygen sensing by hydroxylating an asparagine within HIF-alpha. It also hydroxylates asparagines in many proteins containing ankyrin repeats, including Notch1-3, p105 and I?B?. Relative binding affinity and hydroxylation rate are crucial determinants of substrate selection and modification. We determined the contributions of substrate sequence composition and length and of oxygen concentration to the FIH-1-binding and/or hydroxylation of Notch1-4 and compared them with those for HIF-1alpha. We also demonstrated hydroxylation of two asparagines in Notch2 and 3, corresponding to Sites 1 and 2 of Notch1, by mass spectrometry for the first time. Our data demonstrate that substrate length has a much greater influence on FIH-1-dependent hydroxylation of Notch than of HIF-1alpha, predominantly through binding affinity rather than maximal reaction velocity. The K(m) value of FIH-1 for Notch1, textless 0.2 microM, is at least 250-fold lower than that of 50 microM for HIF-1alpha. Site 1 of Notch1-3 appeared the preferred site of FIH-1 hydroxylation in these substrates. Interestingly, binding of Notch4 to FIH-1 was observed with an affinity almost 10-fold lower than for Notch1-3, but no hydroxylation was detected. Importantly, we demonstrate that the K(m) of FIH-1 for oxygen at the preferred Site 1 of Notch1-3, 10-19 microM, is an order of magnitude lower than that for Site 2 or HIF-1alpha. Hence, at least during in vitro hydroxylation, Notch is likely to become efficiently hydroxylated by FIH-1 even under relatively severe hypoxic conditions, where HIF-1alpha hydroxylation would be reduced.},
note = {Place: Netherlands},
keywords = {alpha Subunit/*metabolism, Amino Acid Sequence, Animals, Asparagine/metabolism, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, Kinetics, Mice, Mixed Function Oxygenases, Molecular Sequence Data, Notch/chemistry/*metabolism, Oxygen/metabolism, Peptides/chemistry/metabolism, PPSE, Protein Binding, Receptors, Recombinant Proteins/metabolism, Repressor Proteins/*metabolism, Substrate Specificity},
pubstate = {published},
tppubtype = {article}
}