Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin

David Kuninger, Robin Kuns-Hashimoto, Mahta Nili, Peter Rotwein

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background. Repulsive guidance molecule c (RGMc or hemojuvelin), a glycosylphosphatidylinositol-linked glycoprotein expressed in liver and striated muscle, plays a central role in systemic iron balance. Inactivating mutations in the RGMc gene cause juvenile hemochromatosis (JH), a rapidly progressing iron storage disorder with severe systemic manifestations. RGMc undergoes complex biosynthetic steps leading to membrane-bound and soluble forms of the protein, including both 50 and 40 kDa single-chain species. Results. We now show that pro-protein convertases (PC) are responsible for conversion of 50 kDa RGMc to a 40 kDa protein with a truncated COOH-terminus. Unlike related molecules RGMa and RGMb, RGMc encodes a conserved PC recognition and cleavage site, and JH-associated RGMc frame-shift mutants undergo COOH-terminal cleavage only if this site is present. A cell-impermeable peptide PC inhibitor blocks the appearance of 40 kDa RGMc in extra-cellular fluid, as does an engineered mutation in the conserved PC recognition sequence, while the PC furin cleaves 50 kDa RGMc in vitro into a 40 kDa molecule with an intact NH2- terminus. Iron loading reduces release of RGMc from the cell membrane, and diminishes accumulation of the 40 kDa species in cell culture medium. Conclusion. Our results define a role for PCs in the maturation of RGMc that may have implications for the physiological actions of this critical iron-regulatory protein.

Original languageEnglish (US)
Article number9
JournalBMC Biochemistry
Volume9
Issue number1
DOIs
StatePublished - 2008

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Iron-Regulatory Proteins
Processing
Proteins
Iron
Molecules
Furin
Glycosylphosphatidylinositols
Mutation
Hemochromatosis
Striated Muscle
Cell membranes
Culture Media
Cell culture
Glycoproteins
Liver
Cell Culture Techniques
Muscle
Cell Membrane
Genes
Peptides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. / Kuninger, David; Kuns-Hashimoto, Robin; Nili, Mahta; Rotwein, Peter.

In: BMC Biochemistry, Vol. 9, No. 1, 9, 2008.

Research output: Contribution to journalArticle

Kuninger, David ; Kuns-Hashimoto, Robin ; Nili, Mahta ; Rotwein, Peter. / Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin. In: BMC Biochemistry. 2008 ; Vol. 9, No. 1.
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