14-3-3 Binding and phosphorylation of neuroglobin during hypoxia modulate six-to-five heme pocket coordination and rate of nitrite reduction to nitric oxide
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Neuroglobin protects neurons from hypoxia in vitro and in vivo; however, the underlying mechanisms for this effect remain poorly understood. Most of the neuroglobin is present in a hexacoordinate state with proximal and distal histidines in the heme pocket directly bound to the heme iron. At equilibrium, the concentration of the five-coordinate neuroglobin remains very low (0.1-5%). Recent studies have shown that post-translational redox regulation of neuroglobin surface thiol disulfide formation increases the open probability of the heme pocket and allows nitrite binding and reaction to form NO. We hypothesized that the equilibrium between the six- and five-coordinate states and secondary reactions with nitrite to form NO could be regulated by other hypoxia-dependent post-translational modification(s). Protein sequence models identified candidate sites for both 14-3-3 binding and phosphorylation. In both in vitro experiments and human SH-SY5Y neuronal cells exposed to hypoxia and glucose deprivation, we observed that 1) neuroglobin phosphorylation and protein-protein interactions with 14-3-3 increase during hypoxic and metabolic stress; 2) neuroglobin binding to 14-3-3 stabilizes and increases the half-life of phosphorylation; and 3) phosphorylation increases the open probability of the heme pocket, which increases ligand binding (CO and nitrite) and accelerates the rate of anaerobic nitrite reduction to form NO. These data reveal a series of hypoxia-dependent post-translational modifications to neuroglobin that regulate the six-to-five heme pocket equilibrium and heme access to ligands. Hypoxia-regulated reactions of nitrite and neuroglobin may contribute to the cellular adaptation to hypoxia.
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Ngb phosphorylation has been shown to increase Ngb reductase activity about four-fold.
“In addition, Ngb phosphorylation has been shown to increase Ngb reductase activity about four-fold [60].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [60]
The affinity of the heme iron for the distal histidine can be increased through protein modification, thereby increasing the rate of nitrite reduction.
“Interestingly, the affinity of the heme iron for the distal histidine can be increased through protein modification, thereby increasing the rate of nitrite reduction [58, 60].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [60]
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- Authors
- Jayaraman, T., Tejero, J., Chen, B. B., Blood, A. B., Frizzell, S., Shapiro, C., Tiso, M., Hood, B. L., Wang, X., Zhao, X., Conrads, T. P., Mallampalli, R. K., & Gladwin, M. T.
- Affiliations
- University of Pittsburgh (US)
- Loma Linda University (US)
- National Institutes of Health (US)
- Corresponding author
- Jayaraman, Thottala
- Gladwin, Mark T.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 286
- Issue
- 49
- Pages
- 42679-42689
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3234913
- OpenAlex
- W2043656884
- Cited by
- 73
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 6 · 2018: 9 · 2017: 8 · 2016: 7 · 2015: 5 · 2014: 2 · 2013: 10 · 2012: 9
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL096973, P01HL103455, R01HL098174, R01HL095973, R01HL097376, R01HL096376, R01HL098032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Keywords
- neuroglobin, 14-3-3 proteins, protein phosphorylation, hypoxia, nitrite reduction, nitric oxide, post-translational modification, neuroprotection, glucose deprivation, SH-SY5Y cells, heme ligand binding, protein-protein interaction
- MeSH terms
- Neuroglobin, Amino Acid Sequence, Animals, Hypoxia, Globins, Heme, Humans, Ligands, Models, Chemical, Molecular Sequence Data, Nerve Tissue Proteins, Nitric Oxide, Nitrites, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Sheep, Protein Interaction Mapping, Fluorescence Resonance Energy Transfer, RNA, Small Interfering, Cell Line, Tumor, 14-3-3 Proteins, Green Fluorescent Proteins
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