Modelling of a metal-containing hepcidin

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Hepcidin is a liver-expressed antimicrobial peptide crucial for iron homeostasis.
• Previous NMR structure revealed a distorted beta-sheet with 4 disulfide bridges, not predicted for metal binding.
• An unusual vicinal disulfide bridge in hepcidin structure was suggested to be functionally significant.

Purpose of the Study:

• To investigate the interaction of hepcidin with iron.
• To explore alternative structural conformations of hepcidin for metal binding.
• To understand the role of hepcidin in iron regulation beyond its antimicrobial function.

Main Methods:

• Co-purification of iron with urine-purified hepcidin peptides (20 and 25 residues).
• Computational modeling: threading hepcidin's primary sequence onto existing 3D folds.
• Generation of a 3D model of hepcidin with bound iron, featuring reduced cysteine residues.

Main Results:

• Iron was successfully co-purified with both 20 and 25 residue hepcidin peptides.
• A novel 3D model of hepcidin was generated, distinct from the synthetic peptide structure, showing reduced cysteines and potential for metal binding.
• The model suggests hepcidin may bind multiple metal atoms due to its short, flexible nature.

Conclusions:

• The co-purification of iron and the new 3D model suggest hepcidin exhibits conformational polymorphism.
• This polymorphism is reminiscent of iron regulatory proteins (IRPs), implying a complex role in iron metabolism.
• Hepcidin's function in iron homeostasis may involve dynamic structural changes facilitating metal interaction.