Understanding the Structure/Activity Relationships of the Iron Regulatory Peptide Hepcidin
| Autor: | Elizabeta Nemeth, Tomas Ganz, David J. Craik, Chia Chia Tan, Richard J. Clark, Gloria C. Preza |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
inorganic chemicals
congenital hereditary and neonatal diseases and abnormalities Iron Overload Iron Clinical Biochemistry Ferroportin Molecular Sequence Data Regulator 01 natural sciences Biochemistry digestive system Article 03 medical and health sciences Selenium Structure-Activity Relationship Hepcidins Hepcidin hemic and lymphatic diseases Drug Discovery Structure–activity relationship Humans Amino Acid Sequence Disulfides Molecular Biology Peptide sequence Cation Transport Proteins 030304 developmental biology Pharmacology 0303 health sciences biology 010405 organic chemistry Chemistry nutritional and metabolic diseases General Medicine 0104 chemical sciences 3. Good health Protein Structure Tertiary Hereditary hemochromatosis biology.protein Molecular Medicine HAMP Homeostasis Antimicrobial Cationic Peptides |
| Popis: | The peptide hormone hepcidin is a key homeostatic regulator of iron metabolism and involved in pathological regulation of iron in response to infection, inflammation, hypoxia and anaemia. It acts by binding to the iron exporter ferroportin, causing it to be internalised and degraded; however, little is known about the structure/activity relationships of the interaction of hepcidin with ferroportin. Here we show that there are key residues within the N-terminal region of hepcidin that influence its interaction with ferroportin, and we explore the structure/function relationships at these positions. We found that the interaction is primarily hydrophobic with critical stereochemical requirements at positions 4 and 6. In addition, a series of hepcidin mutants in which disulfide bonds had been replaced with diselenide bonds showed no change in biological activity compared to native hepcidin. The results provide mechanistic insight into the interaction between hepcidin and ferroportin and identify important constraints for the development of hepcidin congeners for the treatment of hereditary iron overload. |
| Databáze: | OpenAIRE |
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