title: Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239-3098, USA. kuninger@ohsu.edu
authors.forename: David
authors.initials: D
authors.lastname: Kuninger
authors.forename: Robin
authors.initials: R
authors.lastname: Kuns-Hashimoto
authors.forename: Mahta
authors.initials: M
authors.lastname: Nili
authors.forename: Peter
authors.initials: P
authors.lastname: Rotwein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D045683:Furin / Q000378:metabolism; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D007501:Iron / Q000378:metabolism; D035925:Iron-Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D043484:Proprotein Convertases / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*
chemical_list: D045683:Furin; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D007501:Iron; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D043484:Proprotein Convertases; D020033:Protein Isoforms; C504414:HJV protein, mouse