The Solution Structure of Human Hepcidin, a Peptide Hormone with Antimicrobial Activity That Is Involved in Iron Uptake and Hereditary Hemochromatosis
Open accessAbstract
The antibacterial and antifungal peptide hepcidin (LEAP-1) is expressed in the liver. This circulating peptide has recently been found to also act as a signaling molecule in iron metabolism. As such, it plays an important role in hereditary hemochromatosis, a serious iron overload disease. In this study, we report the solution structures of the hepcidin-20 and -25 amino acid peptides determined by standard two-dimensional (1)H NMR spectroscopy. These small cysteine-rich peptides form a distorted beta-sheet with an unusual vicinal disulfide bridge found at the turn of the hairpin, which is probably of functional significance. Both peptides exhibit an overall amphipathic structure with six of the eight Cys involved in maintaining interstrand connectivity. Hepcidin-25 assumes major and minor conformations centered about the Pro residue near the N-terminal end. Further NMR diffusion studies indicate that hepcidin-20 exists as a monomer in solution, whereas hepcidin-25 readily aggregates, a property that may contribute to the different activities of the two peptides. The nuclear Overhauser enhancement spectroscopy spectra of the hepcidin-25 aggregates indicate an interface for peptide interactions that again involves the first five residues from the N-terminal end.
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Inhibition of PIAS3 expression by siRNA resulted in diminished activation of ferritin H transcription in response to ARE-activating agents.
“Inhibition of PIAS3 expression by siRNA resulted in diminished activation of the ferritin H transcription in response to ARE-activating agents (142).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [142]
PIAS3 is an ATF1-binding partner and reverses ATF1-mediated ferritin H ARE repression by blocking ATF1 binding to the ARE.
“protein inhibitor of activated STAT3 (PIAS3) was identified as an ATF1-binding partner and was shown to reverse ATF1-mediated ferritin H ARE repression by blocking ATF1 binding to the ARE (142).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [142]
ATF1 acts as a repressor of the human ferritin H gene through the ARE.
“activating transcription factor 1 (ATF1) was shown to act as a repressor of the human ferritin H gene through the ARE (142)”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [142]
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“This might have caused nonspecific binding of hepcidin, which the molecule is prone to due to its amphipathic character [38].”
Background
- Authors
- Hunter, H. N., Fulton, D. B., Ganz, T., & Vogel, H. J.
- Affiliations
- University of Calgary (CA)
- Iowa State University (US)
- University of California, Los Angeles (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 277
- Issue
- 40
- Pages
- 37597-37603
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2130382251
- Cited by
- 400
- References
- 32
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 9 · 2021: 15 · 2020: 16 · 2019: 17 · 2018: 16 · 2017: 10 · 2016: 17 · 2015: 18 · 2014: 15 · 2013: 17 · 2012: 20
- FWCI
- 9.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Spectroscopy › Advanced NMR Techniques and Applications
- Keywords
- hepcidin, solution structure, iron metabolism, hereditary hemochromatosis, iron overload, antimicrobial peptides, cysteine-rich peptides, peptide aggregation, diffusion NMR
- MeSH terms
- Amino Acid Sequence, Cysteine, Hemochromatosis, Humans, Iron, Models, Molecular, Molecular Sequence Data, Magnetic Resonance Spectroscopy, Oligopeptides, Peptide Fragments, Protein Structure, Secondary, Antimicrobial Cationic Peptides, Hepcidins
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