Cited by 223Cancer, Hypoxia, and MetabolismMetal-Catalyzed Oxygenation MechanismsDevelopmental Biology and Gene Regulation

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Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor

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Coleman, Mathew L., McDonough, Michael A., Hewitson, Kirsty S., Coles, Charlotte, Mecinovicí, Jasmin, Edelmann, Mariola, Cook, Kristina M., Cockman, Matthew E., Lancaster, David E., Kessler, Benedikt M., Oldham, Neil J., Ratcliffe, Peter J., Schofield, Christopher J.·2007·Journal of Biological Chemistry

DOI 10.1074/jbc.m704102200

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Abstract

The stability and activity of hypoxia-inducible factor (HIF) are regulated by the post-translational hydroxylation of specific prolyl and asparaginyl residues. We show that the HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also catalyzes hydroxylation of highly conserved asparaginyl residues within ankyrin repeat (AR) domains (ARDs) of endogenous Notch receptors. AR hydroxylation decreases the extent of ARD binding to FIH while not affecting signaling through the canonical Notch pathway. ARD proteins were found to efficiently compete with HIF for FIH-dependent hydroxylation. Crystallographic analyses of the hydroxylated Notch ARD (2.35A) and of Notch peptides bound to FIH (2.4-2.6A) reveal the stereochemistry of hydroxylation on the AR and imply that significant conformational changes are required in the ARD fold in order to enable hydroxylation at the FIH active site. We propose that ARD proteins function as natural inhibitors of FIH and that the hydroxylation status of these proteins provides another oxygen-dependent interface that modulates HIF signaling.

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Items 101–200 of 223

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“Analysis of the crystal structure of FIH in complex with ankyrin repeat peptide substrates reveals that the ankyrin repeat substrates bind in an elongated conformation, very similar to the way in which HIF-α binds to FIH.1,19 This mode of binding is incompatible with the stereotypical ankyrin fold.”
MethodInfluentialSelf-citation
Complex Energy Landscape of a Giant Repeat Protein
Tsytlonok, M., Craig, P. O., Sivertsson, E. M., Serquera, D., Perrett, S., Best, R. B., Wolynes, P. G., & Itzhaki, L. S. (2013) · Structure · doi:10.1016/j.str.2013.08.028 · Cited by 37
“Impact of Unfolding on the Function of Giant Repeat Proteins In small repeat proteins, the unfolding of the low-stability regions may be important for ligand binding, posttranslational modifications, and translocation (Bergqvist et al., 2009; Coleman et al., 2007; Junker et al., 2006; Kloss and Barrick, 2009; Löw et a…”
Background
Factor inhibiting HIF (FIH-1) promotes renal cancer cell survival by protecting cells from HIF-1α-mediated apoptosis
Khan, M. N., Bhattacharyya, T., Andrikopoulos, P., Esteban, M. A., Barod, R., Connor, T., Ashcroft, M., Maxwell, P. H., & Kiriakidis, S. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.73 · Cited by 40
“1157 British Journal of Cancer (2011) 104(7), 1151 – 1159& 2011 Cancer Research UK M o le c u la r D ia g n o st ic s IkB family of inhibitory proteins and tankyrase (Cockman et al, 2006, 2009; Coleman et al, 2007; Ferguson et al, 2007; Zheng et al, 2008).”
Background
Factor inhibiting HIF1α (FIH-1) functions as a tumor suppressor in human colorectal cancer by repressing HIF1α pathway
Chen, T., Ren, Z., Ye, L., Zhou, P., Xu, J., Shi, Q., Yao, L.-Q., & Zhong, Y. (2015) · Cancer Biology & Therapy · doi:10.1080/15384047.2014.1002346 · Cited by 39
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Schödel, J., Bohr, D., Klanke, B., Schley, G., Schlötzer-Schrehardt, U. M., Warnecke, C., Kurtz, A., Amann, K., Eckardt, K., & Willam, C. (2010) · Kidney International · doi:10.1038/ki.2010.284 · Cited by 40
“FIH1 has been proposed to have numerous other targets, including, in particular, ankyrin repeat domains of proteins such as p105 as a precursor of the p50 subunit of nuclear factor-kB, Ik-Ba, or the notch receptor.(18,19) The physiological role of the ankyrin hydroxylation is presently not clear, FIH1”
Background
Substrate Selectivity Analyses of Factor Inhibiting Hypoxia‐Inducible Factor
Yang, M. H., Hardy, A., Chowdhury, R., Loik, N. D., Scotti, J. S., McCullagh, J., Claridge, T. D. W., McDonough, M. A., Ge, W., & Schofield, C. J. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201208046 · Cited by 38
Self-citation
Interaction of the Ankyrin H Core Effector of Legionella with the Host LARP7 Component of the 7SK snRNP Complex
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Oxygen-dependent hydroxylation by Factor Inhibiting HIF (FIH) regulates the TRPV3 ion channel
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“…are substrates for asparaginyl hydroxylation by FIH, including IKba, p105, Notch and ASPP2 (also known as TP53BP2) (Cockman et al., 2006; Cockman et al., 2009; Coleman et al., 2007; Janke et al., 2013; Zheng et al., 2008), but the functional consequences of hydroxylation remain unclear.”
BackgroundInfluential
Inhibitor of nuclear factor‐kappaB alpha derepresses hypoxia‐inducible factor‐1 during moderate hypoxia by sequestering factor inhibiting hypoxia‐inducible factor from hypoxia‐inducible factor 1α
Shin, D. H., Li, S. H., Yang, S., Lee, B. L., Lee, M. K., & Park, J. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07069.x · Cited by 38
Biochemical and structural investigations clarify the substrate selectivity of the 2-oxoglutarate oxygenase JMJD6
Islam, M. S., McDonough, M. A., Chowdhury, R., Gault, J., Khan, A. P., Pires, E., & Schofield, C. J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.008693 · Cited by 37
“FIH catalyzes the C-3 hydroxylation of an asparagine residue in the hypoxia-inducible transcription factor (HIF), a modification that serves to regulate the transcriptional activity of HIF, as well as various residues in ankyrin repeat domain proteins (8, 9).”
BackgroundSelf-citation
Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells
Bock, K. D., Smet, F. D., de Oliveira, R. L., Anthonis, K., & Carmeliet, P. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0482-z · Cited by 39
“Finally, FIH-1 also hydroxylates the Notch intracellular domain, and independently from its hydroxylation status, their interaction negatively regulates Notch-signaling [ 74 , 75].”
Background
2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases
Nakashima, Y., Brewitz, L., Tumber, A., Salah, E., & Schofield, C. J. (2021) · Nature Communications · doi:10.1038/s41467-021-26673-2 · Cited by 38
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Overexpression of factor inhibiting HIF‐1 enhances vessel maturation and tumor growth via platelet‐derived growth factor‐C
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Kinetic parameters of human aspartate/asparagine–β-hydroxylase suggest that it has a possible function in oxygen sensing
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“By contrast, FIH is less susceptible to hypoxia (27, 30–32) and catalyzes the hydroxylation of other substrates than HIF, often from the ankyrin repeat domain– containing family of proteins (33, 34), where it can catalyze the hydroxylation of not only asparaginyl residues, but (like AspH) also of other residues includ…”
BackgroundSelf-citation
New Classes of Mind Bomb-Interacting Proteins Identified from Yeast Two-Hybrid Screens
Tseng, L.-C., Zhang, C., Cheng, C.-M., Xu, H., Hsu, C.-H., & Jiang, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093394 · Cited by 33
“Recently, Fih-1 was found that it can associate with and hydroxylate proteins containing AND, such as Notch receptor 1, 2 and 3 [43], IkBa [44], and Tankyrase-2, Rabankyrin-5 and RNase L [45].”
Background
Interactions between Notch- and hypoxia-induced transcriptomes in embryonic stem cells
Main, H., Lee, K. L., Yang, H. H., Haapa-Paananen, S. M., Edgren, H., Jin, S., Sahlgren, C., Kallioniemi, O., Poellinger, L., Lim, B., et al. (2009) · Experimental Cell Research · doi:10.1016/j.yexcr.2009.12.012 · Cited by 33
Notch signalling in ischaemia-induced angiogenesis
Zen, A. A. H., & Madeddu, P. R. (2009) · Biochemical Society Transactions · doi:10.1042/bst0371221 · Cited by 31
“Interestingly, FIH-1 is also able to hydroxylate NICD [38].”
Factor‐inhibiting HIF‐1 (FIH‐1) is required for human vascular endothelial cell survival
Kiriakidis, S., Henze, A., Kruszynska‐Ziaja, I., Skobridis, K., Theodorou, V., Paleolog, E. M., & Mazzone, M. (2015) · The FASEB Journal · doi:10.1096/fj.14-252379 · Cited by 32
“Abbreviations: ARD, ankyrin repeat domain; Asn, asparagine; Bax, B cell lymphoma 2-associated X protein; Bcl-2, B cell lymphoma 2; Bcl-xL, B cell lymphoma-extra large; BNIP-3, B cell lymphoma/adenovirus E1B 19 kDa protein-interacting protein; CBP, cAMP response element-binding protein; CDC, cell division cycle; CI, ce…”
BackgroundInfluential
The interplay between the cellular hypoxic response and Notch signaling
Landor, S. K.-J., & Lendahl, U. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.04.030 · Cited by 33
Factor Inhibiting HIF (FIH) Recognizes Distinct Molecular Features within Hypoxia-inducible Factor-α (HIF-α) versus Ankyrin Repeat Substrates
Wilkins, S. E., Karttunen, S., Hampton‐Smith, R. J., Murchland, I., Chapman‐Smith, A., & Peet, D. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.294678 · Cited by 29
“Althoughboth proteins contain seven ankyrin repeats, theARD of Notch1 contains two Asn residues (Asn-1945/2012) that are targeted for hydroxylation by FIH (10, 34), whereas a single Asn residue in Gankyrin (Asn-100) is hydroxylated (Ref.”
BackgroundMethodResultInfluential
MYPT1, the targeting subunit of smooth-muscle myosin phosphatase, is a substrate for the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH)
Webb, J. D., Murányi, A., Pugh, C. W., Ratcliffe, P. J., & Coleman, M. L. (2009) · Biochemical Journal · doi:10.1042/bj20081905 · Cited by 28
Self-citation
Notch Signaling and Cross-Talk in Hypoxia: A Candidate Pathway for High-Altitude Adaptation
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“FIH-1 hydroxylates the Notch ICD at two conserved asparagine residues (N1945 and N2012) [45,94], binding with a higher affinity than it does to HIF-1α [45].”
Background
Oxygen Sensing: A Common Crossroad in Cancer and Neurodegeneration
Quaegebeur, A., & Carmeliet, P. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_83 · Cited by 27
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Lanner, F., Lee, K. L., Ortega, G. C., Sohl, M., Li, X., Jin, S., Hansson, E. M., Claesson, L., Poellinger, L., Lendahl, U., et al. (2013) · Stem Cells and Development · doi:10.1089/scd.2012.0259 · Cited by 27
“This includes the interaction between HIF and Notch ICD, and the enzymatic modiﬁcation of both HIF and Notch ICD by FIH [19–21].”
Copper-enriched automotive brake wear particles perturb human alveolar cellular homeostasis
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“For the HIF-CAD reporter assay [29] (measuring FIH activity), 225 ng GAL4-DBD-HIF1α-CAD plasmid was added along with 225 ng UAS-luciferase plasmid, and 50 ng Renilla luciferase per well.”
Influential
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Lv, S., Cheng, G., Zhou, Y., & Xu, G. (2013) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-013-1713-8 · Cited by 26
“[20] suggested that NICD has a greater affinity for binding with the HIF-1a inhibiting factor, FIH-1, and that this may indirectly prevent FIH-1-mediated HIF-1a degradation.”
Background
Inverse Solvent Isotope Effects Arising from Substrate Triggering in the Factor Inhibiting Hypoxia Inducible Factor
Hangasky, J. A., Saban, E., & Knapp, M. J. (2013) · Biochemistry · doi:10.1021/bi3015482 · Cited by 26
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“Importantly, mass spectroscopic evidence for hydroxylation of ankyrin repeats in IkB and nuclear factor kB family members, as well as in ASB4, a suppressor of cytokine signaling, by FIH showed that hydroxylation is not restricted to HIF-a subunits (Coleman et al., 2007; Ferguson et al., 2007).”
Background
Consequences of IkappaB alpha hydroxylation by the factor inhibiting HIF (FIH)
DeVries, I. L., Hampton‐Smith, R. J., Mulvihill, M. M., Alverdi, V., Peet, D. J., & Komives, E. A. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.10.060 · Cited by 25
“Searches for alternative substrates of FIH identified IκB and Notch family members and ASB4 (ankyrin repeat and SOCS box protein 4) as substrates of FIH [5-10].”
Quantitative Mass Spectrometry Reveals Dynamics of Factor-inhibiting Hypoxia-inducible Factor-catalyzed Hydroxylation
Singleton, R. S., Trudgian, D. C., Fischer, R., Kessler, B. M., Ratcliffe, P. J., & Cockman, M. E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.262808 · Cited by 25
Self-citation
A Notch-independent mechanism contributes to the induction of Hes1 gene expression in response to hypoxia in P19 cells
Zheng, X., Narayanan, S., Zheng, X., Luecke-Johansson, S., Gradin, K., Catrina, S., Poellinger, L., & Pereira, T. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.06.006 · Cited by 23
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“htm, [160–167].”
Oxygen sensor FIH inhibits HACE1-dependent ubiquitination of Rac1 to enhance metastatic potential in breast cancer cells
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FIH-1-Mint3 Axis Does Not Control HIF-1α Transcriptional Activity in Nucleus Pulposus Cells
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“Given the number of genes affected by FIH-1 silencing in NP cells, including those concerned with the Notch pathway, and in recognition of the fact that FIH-1 is known to hydroxylate many proteins with ankyrin repeats, including p105, I B (40), and members of the Notch receptor family (41), it is very plausible that m…”
Background
Hypoxia-Inducible Lysine Methyltransferases: G9a and GLP Hypoxic Regulation, Non-histone Substrate Modification, and Pathological Relevance
Chopra, A., Cho, W. C. S., Willmore, W. G., & Biggar, K. K. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.579636 · Cited by 24
FIH-1/c-Kit Signaling: A Novel Contributor to Corneal Epithelial Glycogen Metabolism
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“It is important to note that all of the experiments were conducted under normoxic conditions, which is the usual state of the corneal epithelium and when FIH-1 is active.(32,35) In”
Background
Review article: How cells sense oxygen: Lessons from and for the kidney
Gleadle, J. (2009) · Nephrology · doi:10.1111/j.1440-1797.2008.01064.x · Cited by 18
Combined proteomic and biochemical analyses redefine the consensus sequence requirement for epidermal growth factor-like domain hydroxylation
Brewitz, L., Onisko, B., & Schofield, C. J. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102129 · Cited by 19
Self-citation
Hydroxylation of the NOTCH1 intracellular domain regulates Notch signaling dynamics
Ferrante, F., Giaimo, B. D., Friedrich, T., Sugino, T., Mertens, D., Kugler, S. J., Gahr, B. M., Just, S., Pan, L., Bartkuhn, M., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05052-9 · Cited by 17
The catalytic domains of all human KDM5 JmjC demethylases catalyse N‐methyl arginine demethylation
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Self-citation
Structure-guided optimisation of N -hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-α
Corner, T. P., Teo, R. Z. R., Wu, Y., Salah, E., Nakashima, Y., Fiorini, G., Tumber, A., Brasnett, A., Holt‐Martyn, J. P., Figg, W. D., et al. (2023) · Chemical Science · doi:10.1039/d3sc04253g · Cited by 17
“43 FIH is also reported to catalyse the C3 hydroxylation of residues other than asparagine, including histidine, 44 tryptophan-45,46 and aspartate-residues.”
BackgroundSelf-citation
Self-hydroxylation of the splicing factor lysyl hydroxylase, JMJD6
Mantri, M., Webby, C. J., Loik, N. D., Hamed, R. B., Nielsen, M. L., McDonough, M. A., McCullagh, J., Böttger, A., Schofield, C. J., & Wolf, A. (2011) · MedChemComm · doi:10.1039/c1md00225b · Cited by 17
Self-citation
Ankyrin Repeat Proteins of Orf Virus Influence the Cellular Hypoxia Response Pathway
Chen, D. W., Fabrizio, J.-A., Wilkins, S. E., Dave, K. A., Gorman, J. J., Gleadle, J., Fleming, S. B., Peet, D. J., & Mercer, A. A. (2016) · Journal of Virology · doi:10.1128/jvi.01430-16 · Cited by 17
“This is consistent with the proposed role for FIH-dependent hydroxylation of cellular ANK proteins in regulating HIF activity through sequestration of FIH (36).”
Background
Predicting repeat protein folding kinetics from an experimentally determined folding energy landscape
Street, T. O., & Barrick, D. (2008) · Protein Science · doi:10.1002/pro.9 · Cited by 16
The expanding universe of hypoxia
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“Novel substrates for the HIF asparaginyl hydroxylase FIH-1 include Notch, tankyrase, and IκBα [2, 3].”
Background
The role of ankyrin repeat-containing proteins in epigenetic and transcriptional regulation
Wu, M., Zhao, Y., Yang, J., Yang, F., Dai, Y., Wang, Q., Chen, C., & Chu, X. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02519-4 · Cited by 16
The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease
Townley-Tilson, W. H. D., Pi, X., & Xie, L. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/676893 · Cited by 15
“Adding to the complexity of FIH-mediated hydroxylation is its ability to hydroxylatemembers of the ankyrin repeat family of proteins including the NF-𝜅B inhibitor I𝜅B [104], the receptor protein Notch [105], and the vascular E3 ligase ankyrin repeat and SOCS box containing 6 4 (ASB4) [106], which appears to regulate t…”
Background
The facial triad in the α-ketoglutarate dependent oxygenase FIH: A role for sterics in linking substrate binding to O2 activation
Hangasky, J. A., Taabazuing, C. Y., Martin, C. B., Eron, S. J., & Knapp, M. J. (2016) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2016.10.007 · Cited by 15
Factor-inhibiting HIF (FIH) promotes lung cancer progression
Río, A. G.-D., Prieto‐Fernández, E., Egia‐Mendikute, L., Antoñana-Vildosola, A., Jiménez-Lasheras, B., Lee, S. Y., Barreira-Manrique, A., Zanetti, S. R., de Blas, A., Velasco-Beltrán, P., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.167394 · Cited by 14
A novel HIF1AN substrate KANK3 plays a tumor‐suppressive role in hepatocellular carcinoma
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“Of note, the hydroxylation efficiency of HIF1AN substrates in vitro does not correlate with the binding affinity or enzymatic activity within cells, as shown in previous studies on other substrates such as Notch ARDs (Coleman et al., 2007).”
Result
Molecular response and association analysis of Megalobrama amblycephala fih-1 with hypoxia
Zhang, B., Chen, N., Huang, C., Huang, C., Chen, B.-X., Liu, H., Wang, W., Gul, Y., & Wang, H. (2016) · Molecular Genetics and Genomics · doi:10.1007/s00438-016-1208-x · Cited by 14
A human protein hydroxylase that accepts D-residues
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Self-citation
Analyzing the Posttranslational Modification Status of Notch Using Mass Spectrometry
Kakuda, S., & Haltiwanger, R. S. (2014) · Methods in molecular biology · doi:10.1007/978-1-4939-1139-4_16 · Cited by 13
Exploring links between 2‐oxoglutarate‐dependent oxygenases and Alzheimer's disease
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Self-citation
Subdomain Architecture and Stability of a Giant Repeat Protein
Tsytlonok, M., Sormanni, P., Rowling, P. J. E., Vendruscolo, M., & Itzhaki, L. S. (2013) · The Journal of Physical Chemistry B · doi:10.1021/jp402360x · Cited by 12
The conservation and functionality of the oxygen-sensing enzyme Factor Inhibiting HIF (FIH) in non-vertebrates
Hampton‐Smith, R. J., Davenport, B. A., Nagarajan, Y., & Peet, D. J. (2019) · PLoS ONE · doi:10.1371/journal.pone.0216134 · Cited by 11
“Alternatively, it has been proposed that ARDs function collectively as a “sink” which sequesters FIH protein away from HIF-1 α , thus regulating HIF activity [12, 18].”
Biological Regulation via Ankyrin Repeat Folding
Barrick, D. (2009) · ACS Chemical Biology · doi:10.1021/cb900003f · Cited by 11
“Recently, the Notch ankyrin domain was shown to be hydroxylated at one or more asparagine C s (19, 20).”
The Role of 2-Oxoglutarate-Dependent Oxygenases in Hypoxia Sensing
Wilkins, S. E., Flashman, E., Scotti, J. S., Hopkinson, R. J., Chowdhury, R., & Schofield, C. J. (2015) · Royal Society of Chemistry eBooks · doi:10.1039/9781782621959-00169 · Cited by 10
Self-citation
Nuclear entry and export of FIH are mediated by HIF1α and exportin1, respectively
Wang, Y., Zhong, S., Schofield, C. J., Ratcliffe, P. J., & Lü, X. (2018) · Journal of Cell Science · doi:10.1242/jcs.219782 · Cited by 10
“Subsequent work has also revealed that FIH accepts multiple substrates from the ankyrin repeat domain (ARD) family of proteins (Cockman et al., 2006, 2009; Coleman et al., 2007; Janke et al., 2013; Karttunen et al., 2015; Zheng et al., 2008), which are located in different cellular compartments.”
BackgroundMethodInfluentialSelf-citation
Investigations on the role of a solvent tunnel in the α-ketoglutarate dependent oxygenase factor inhibiting HIF (FIH)
Chaplin, V. D., Valliere, M. A., Hangasky, J. A., & Knapp, M. J. (2017) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2017.10.001 · Cited by 9
Studies on substrate specificity of Jmjd2a-c histone demethylases
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“Therefore, these enzymes generally have lax substrate specificities [13–15], suggesting KDMs may have additional non-histone substrates.”
Background
Light-Induced, Lysine-Targeting Irreversible Covalent Inhibition of the Human Oxygen Sensing Hydroxylase Factor Inhibiting HIF (FIH)
Wu, Y., Li, Z., Kaur, S., Zhang, Z., Yue, J., Tumber, A., Zhang, H., Song, Z., Yang, P., Dong, Y., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c01935 · Cited by 9
Self-citation
Factor inhibiting HIF can catalyze two asparaginyl hydroxylations in VNVN motifs of ankyrin fold proteins
Leissing, T. M., Hardy, A., Chan, H. F., Wang, Y., Tumber, A., Chowdhury, R., Feng, T., Coleman, M. L., Cockman, M. E., Kramer, H., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102020 · Cited by 10
“These observations are in accord with proposals that enzyme–substrate interactions relatively distant from the FIH active site, likely involving at least partial unfolding of the stereotypically observed ARD conformation, are involved in regulating catalysis by FIH (13, 31).”
BackgroundSelf-citation
Synthesis and conformational analysis of cyclic analogues of inverse γ-turns
Kaewpet, M., Odell, B., King, M. A., Banerji, B., Schofield, C. J., & Claridge, T. D. W. (2008) · Organic & Biomolecular Chemistry · doi:10.1039/b808954j · Cited by 9
Self-citation
Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat
Corner, T. P., Salah, E., Tumber, A., Kaur, S., Nakashima, Y., Allen, M. D., Schnaubelt, L. I., Fiorini, G., Brewitz, L., & Schofield, C. J. (2024) · ChemMedChem · doi:10.1002/cmdc.202400504 · Cited by 10
Self-citation
Prevention of apoptosis by the interaction between FIH1 and Bax
Yan, B., Kong, M., & Chen, Y. (2010) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-010-0631-2 · Cited by 8
“Affinity measurements also indicate that FIH1 has higher affinity with some ARDs than does HIF1-a [ 6 , 7], implicating that FIH1 may be involved in the regulation of the functions of ARD-containing proteins.”
Background
To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families
Nisio, E. D., Manzini, V., Licursi, V., & Negri, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25136900 · Cited by 7
“It has been recently shown that both wild-type and catalytically inactive mutants of JMJD5 cooperate with E3 ligase HUWE1 to destabilize EGFR and EGFR tyrosine kinase inhibitor-resistant mutants for proteasomal degradation in lung cancer cells [110].”
Background
From Artificial Antibodies to Nanosprings
Itzhaki, L. S., & Lowe, A. R. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3229-6_10 · Cited by 7
Cellular and Molecular Defenses Against Hypoxia
Frede, S., & Fandrey, J. (2013) · Springer eBooks · doi:10.1007/978-1-4614-8772-2_2 · Cited by 8
Mitochondria, oxygen sensing, and the regulation of HIF-2α. Focus on “Induction of HIF-2α is dependent on mitochondrial O2 consumption in an O2-sensitive adrenomedullary chromaffin cell line”
Taylor, C. T. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00206.2008 · Cited by 7
“Furthermore, the regulation of gene expression in response to hypoxia is not confined to the HIF pathway; for example, a number of other transcription factors, including NF- B and Notch, have been shown to be hypoxia sensitive in a hydroxylase-dependent manner (2, 3, 5, 14).”
Background
Substrate Positioning by Gln239 Stimulates Turnover in Factor Inhibiting HIF, an αKG-Dependent Hydroxylase
Hangasky, J. A., Ivison, G. T., & Knapp, M. J. (2014) · Biochemistry · doi:10.1021/bi500703s · Cited by 6
Substrate Selectivity Analyses of Factor Inhibiting Hypoxia‐Inducible Factor
Yang, M. H., Hardy, A., Chowdhury, R., Loik, N. D., Scotti, J. S., McCullagh, J., Claridge, T. D. W., McDonough, M. A., Ge, W., & Schofield, C. J. (2013) · Angewandte Chemie · doi:10.1002/ange.201208046 · Cited by 6
Self-citation
Enzymes involved in hypoxia response : characterization of the in vivo role of HIF-P4H-2 in mouse heart, of a novel P4H in human and zebrafish and of the catalytic properties of FIH
Hyvärinen, J. (2010) · Cited by 6
Adventures in Defining Roles of Oxygenases in the Regulation of Protein Biosynthesis
Walport, L. J., & Schofield, C. J. (2018) · The Chemical Record · doi:10.1002/tcr.201800056 · Cited by 5
Self-citation
Methods for production and assaying catalysis of isolated recombinant human aspartate/asparagine-β-hydroxylase
Brewitz, L., Brasnett, A., Schnaubelt, L. I., Rabe, P., Tumber, A., & Schofield, C. J. (2024) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2024.06.003 · Cited by 4
Self-citation
Structural and functional consequences of aspartate/asparagine-β-hydroxylase variants causing Traboulsi syndrome
Hou, C., Brasnett, A., Rabe, P., Schofield, C. J., & Brewitz, L. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.111008 · Cited by 3
“Given that wt AspH acts on multiple EGFDs, the specific set of EGFDs involved in Traboulsi syndrome is hard to define, with competition be-tween substrates, as proposed for FIH, being a possible factor (61).”
Self-citation
Dietary Soy Preserves Cognitive Function in Experimental Fetal Alcohol Spectrum Disorder: Role of Increased Signaling through Notch and Gonadotropin Releasing Hormone Networks
de la Monte, S. M., Tong, M., Ziplow, J. L., Mark, P., Van, S., & Nguyen, V. A. (2025) · Journal of Behavioral and Brain Science · doi:10.4236/jbbs.2025.152002 · Cited by 3
“Finally, FIH, which like ASPH, has hydroxylase catalytic functions, negatively regulates crosstalk between HIF and Notch by asparaginyl hydroxylation of the Notch ICD, inhibiting HIF activation of Notch [80] [81].”
Structural Biology of Notch Signaling
Arnett, K. L., Seegar, T. C. M., & Blacklow, S. C. (2018) · Springer eBooks · doi:10.1007/978-1-4939-8859-4_1 · Cited by 3
Kinetic Studies of the Hydrogen Atom Transfer in a Hypoxia-Sensing Enzyme, FIH-1: KIE and O2 Reactivity
Mingroni, M. A., & Knapp, M. J. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00476 · Cited by 3
Biochemical and Structural Insights into FIH‐Catalysed Hydroxylation of Transient Receptor Potential Ankyrin Repeat Domains
Saward, B. G., Leissing, T. M., Clifton, I. J., Tumber, A., Timperley, C. M., Hopkinson, R. J., & Schofield, C. J. (2022) · ChemBioChem · doi:10.1002/cbic.202200576 · Cited by 2
Self-citation
The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinomaPreprint
Meisel, C. T., Destefani, R., Valookkaran, I. J., Rupp, N. J., Batavia, A. A., Catto, F., Hofmann-Lobsiger, J., Mitsiadis, T. A., & Porcheri, C. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.21.576524 · Cited by 3
Mechanistic Basis of Bifunctional Oxidation by a Non-Heme Fe(II)/2-Oxoglutarate-Dependent Enzyme CcTET toward N 6-Methyladenine and 5-Methylcytosine in Double-Stranded DNA
Varada, B., Rifayee, S. B. J. S., Thomas, M. G., Sommer, E., Davis, C., Waheed, S. O., Devadas, S., Kalita, S., Melayikandy, S., Karabencheva‐Christova, T. G., et al. (2026) · ACS Catalysis · doi:10.1021/acscatal.6c02591 · Cited by 4
Sirtuin1 meditated modification of Notch1 intracellular domain regulates nucleolar localization and activation of distinct signaling cascades
Saini, N., Bheeshmachar, G., & Sarin, A. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.988816 · Cited by 2
“Notch receptors are modified by acetylation, fucosylation, phosphorylation, methylation, hydroxylation, and sumoylation (Coleman et al., 2007; Fortini 2009; Ishitani et al., 2010; Guarani et al., 2011; Popko-Scibor et al., 2011; Ranganathan et al., 2011; Antila et al., 2018).”
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Recent Advances and Therapeutic Implications of 2-Oxoglutarate-Dependent Dioxygenases in Ischemic Stroke
Xie, J. M., & Zhang, Z. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03790-1 · Cited by 3
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Impact of Prenatal Dietary Soy on Cerebellar Neurodevelopment and Function in Experimental Fetal Alcohol Spectrum Disorder
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“Finally, the factor inhibiting HIF-1 (FIH), which like ASPH, has hydroxylase catalytic functions, mediates negatively regulated crosstalk between HIF and Notch by asparaginyl hydroxylation of the Notch ICD thereby inhibiting HIF activation of Notch [74,75].”
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Authors: Coleman, M. L., McDonough, M. A., Hewitson, K. S., Coles, C., Mecinovicí, J., Edelmann, M., Cook, K. M., Cockman, M. E., Lancaster, D. E., Kessler, B. M., Oldham, N. J., Ratcliffe, P. J., & Schofield, C. J.
Affiliations: University of Oxford (GB)
Corresponding author: Schofield, Christopher J.
ORCID: Coleman, Mathew L.
McDonough, Michael A.
Coles, Charlotte
Cook, Kristina M.
Cockman, Matthew E.
Kessler, Benedikt M.
Oldham, Neil J.
Ratcliffe, Peter J.
Schofield, Christopher J.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2007-08
Volume: 282
Issue: 33
Pages: 24027-24038
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m704102200
OpenAlex: W2078263362
Cited by: 222
References: 34
Citations by year: 2026: 1 · 2025: 7 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 19 · 2012: 11
FWCI: 8.31
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4793 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders: Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBS/B/07683)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords: FIH, Notch receptor, ankyrin repeat domain, hypoxia-inducible factor, protein stability, oxygen sensing, protein-protein interaction, conformational change, crystal structure, Notch signaling
MeSH terms: Receptor, Notch3, Asparagine, Humans, Mixed Function Oxygenases, Hydroxylation, Repressor Proteins, Transcription Factors, Ankyrin Repeat, Protein Structure, Tertiary, Crystallography, X-Ray, Hypoxia-Inducible Factor 1, alpha Subunit, Receptors, Notch, Receptor, Notch1, Receptor, Notch2

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Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor

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