Journal of Molecular Evolution

, Volume 65, Issue 1, pp 68–81

Molecular Evolution of Hemojuvelin and the Repulsive Guidance Molecule Family

Article

Abstract

Repulsive guidance molecules (RGMs) are found in vertebrates and chordates and are involved in embryonic development and iron homeostasis. Members of this family are GPI-linked membrane proteins that contain an N-terminal signal peptide, a C-terminal propeptide, and a conserved RGD motif. Vertebrates are known to possess three paralogues; RGMA and RGMB (sometimes called Dragon) are expressed in the nervous system and are thought to play various roles in neural development. Hemojuvelin (HJV; also called repulsive guidance molecule c, RGMC) is the third member of this family, and mutations in this gene result in a form of juvenile hemochromatosis (type 2A). Phylogenetic analyses of 55 different RGM family sequences from 21 different species support the existence of a novel gene, found only in fish, which we have labeled RGMD. The pattern of conserved residues in each family identifies new candidates for important functional roles, including ligand binding.

Keywords

Hemojuvelin Repulsive guidance molecule Bone morphogenetic protein Hemochromatosis Iron homeostasis RGD motif Cell signaling 

References

  1. Abascal F, Zardoya R, Posada D (2005) ProtTest: selection of best-fit models of protein evolution. Bioinformatics 21:2104–2105PubMedCrossRefGoogle Scholar
  2. Akiyama Y, Onizuka K, Noguchi T, Ando M (1998) Parallel Protein Information Analysis (PAPIA) system running on a 64-node PC Cluster. In: Proceedings of the 9th Genome Informatics Workshop, pp 131–140Google Scholar
  3. Altschul S, Madden T, Schaffer A, Zhang J, Zhang Z, Miller W, Lipman D (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402PubMedCrossRefGoogle Scholar
  4. Amores A, Force A, Yan YL, Joly L, Amemiya C, Fritz A, Ho RK, Langeland J, Prince V, Wang YL, Westerfield M, Ekker M, Postlethwait JH (1998) Zebrafish hox clusters and vertebrate genome evolution. Science 282:1711–1714PubMedCrossRefGoogle Scholar
  5. Babitt JL, Zhang Y, Samad TA, Xia Y, Tang J, Campagna JA, Schneyer AL, Woolf CJ, Lin HY (2005) Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem 280:29820–29827PubMedCrossRefGoogle Scholar
  6. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY (2006) Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38:531–539PubMedCrossRefGoogle Scholar
  7. Bendtsen JD, Nielsen H, von Heijne G, Brunak S (2004) Improved prediction of signal peptides: SignalP 3.0. J Mol Biol 340:783–795PubMedCrossRefGoogle Scholar
  8. Berezin C, Glaser F, Rosenberg J, Paz I, Pupko T, Fariselli P, Casadio R, Ben-Tal N (2004) ConSeq: the identification of functionally and structurally important residues in protein sequences. Bioinformatics 20:1322–1324PubMedCrossRefGoogle Scholar
  9. Cai W, Pei J, Grishin NV (2004) Reconstruction of ancestral protein sequences and its applications. BMC Evol Biol 4:33PubMedCrossRefGoogle Scholar
  10. Camaschella C (2005) Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 106:3710–3717PubMedCrossRefGoogle Scholar
  11. Collins JF (2006) Gene chip analyses reveal differential genetic responses to iron deficiency in rat duodenum and jejunum. Biol Res 39:25–37PubMedGoogle Scholar
  12. Curran AR, Engelman DM (2003) Sequence motifs, polar interactions and conformational changes in helical membrane proteins. Curr Opin Struct Biol 13:412–417PubMedCrossRefGoogle Scholar
  13. Darras S, Nishida H (2001) The BMP signaling pathway is required together with the FGF pathway for notochord induction in the ascidian embryo. Development 128:2629–2638PubMedGoogle Scholar
  14. De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, Politou M, Lockitch G, Girelli D, Fargion S, Cox TM, Gasparini P, Cazzola M, Camaschella C (2002) Natural history of juvenile haemochromatosis. Br J Haematol 117:973–979PubMedCrossRefGoogle Scholar
  15. Doya H, Ito T, Hata K, Fujitani M, Ohtori S, Saito-Watanabe T, Moriya H, Takahashi K, Kubo T, Yamashita T (2006) Induction of repulsive guidance molecule in neurons following sciatic nerve injury. J Chem Neuroanat 32:74–77PubMedCrossRefGoogle Scholar
  16. D’Souza SE, Ginsberg MH, Plow EF (1991) Arginyl-glycyl-aspartic acid (RGD): a cell adhesion motif. Trends Biochem Sci 16:246–250PubMedCrossRefGoogle Scholar
  17. Durand E, Grinda JM, Bruneval P (2003) Cardiogenic shock in a young woman revealing juvenile haemochromatosis. Heart 89:870PubMedCrossRefGoogle Scholar
  18. Eisenhaber B, Bork P, Eisenhaber F (1999) Prediction of potential GPI-modification sites in proprotein sequences. J Mol Biol 292:741–758PubMedCrossRefGoogle Scholar
  19. Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 95:1472–1477PubMedCrossRefGoogle Scholar
  20. Finn RD, Mistry J, Schuster-Bockler B, Griffiths-Jones S, Hollich V, Lassmann T, Moxon S, Marshall M, Khanna A, Durbin R, Eddy SR, Sonnhammer EL, Bateman A (2006) Pfam: clans, web tools and services. Nucleic Acids Res 34:D247–D251PubMedCrossRefGoogle Scholar
  21. Fitzgerald DP, Seaman C, Cooper HM (2006) Localization of Neogenin protein during morphogenesis in the mouse embryo. Dev Dyn 235:1720–1725PubMedCrossRefGoogle Scholar
  22. Garnier J, Gibrat JF, Robson B (1996) GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol 266:540–553PubMedCrossRefGoogle Scholar
  23. Guindon S, Lethiec F, Duroux P, Gascuel O (2005) PHYML Online––a web server for fast maximum likelihood-based phylogenetic inference. Nucleic Acids Res 33:W557–W559PubMedCrossRefGoogle Scholar
  24. Harada Y, Shoguchi E, Taguchi S, Okai N, Humphreys T, Tagawa K, Satoh N (2002) Conserved expression pattern of BMP-2/4 in hemichordate acorn worm and echinoderm sea cucumber embryos. Zool Sci 19:1113–1121PubMedCrossRefGoogle Scholar
  25. Ito T, Lai MM (1997) Determination of the secondary structure of and cellular protein binding to the 3’-untranslated region of the hepatitis C virus RNA genome. J Virol 71:8698–8706PubMedGoogle Scholar
  26. Jain RG, Rusch SL, Kendall DA (1994) Signal peptide cleavage regions. Functional limits on length and topological implications. J Biol Chem 269:16305–16310PubMedGoogle Scholar
  27. Jones DT, Taylor WR, Thornton JM (1992) The rapid generation of mutation data matrices from protein sequences. Comput Appl Biosci 8:275–282PubMedGoogle Scholar
  28. Keeling SL, Gad JM, Cooper HM (1997) Mouse Neogenin, a DCC-like molecule, has four splice variants and is expressed widely in the adult mouse and during embryogenesis. Oncogene 15:691–700PubMedCrossRefGoogle Scholar
  29. Krijt J, Vokurka M, Chang KT, Necas E (2004) Expression of Rgmc, the murine ortholog of hemojuvelin gene, is modulated by development and inflammation, but not by iron status or erythropoietin. Blood 104:4308–4310PubMedCrossRefGoogle Scholar
  30. Kumar S, Tamura K, Nei M (2004) MEGA3: integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform 5:150–163PubMedCrossRefGoogle Scholar
  31. Lambert LA, Mitchell SL (2007) Molecular evolution of the transferrin receptor/glutamate carboxypeptidase II family. J Mol Evol 64:113–128PubMedCrossRefGoogle Scholar
  32. Lanzara C, Roetto A, Daraio F, Rivard S, Ficarella R, Simard H, Cox TM, Cazzola M, Piperno A, Gimenez-Roqueplo AP, Grammatico P, Volinia S, Gasparini P, Camaschella C (2004) Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 103:4317–4321PubMedCrossRefGoogle Scholar
  33. Liang C, Hu J, Whitney JB, Kleiman L, Wainberg MA (2003) A structurally disordered region at the C terminus of capsid plays essential roles in multimerization and membrane binding of the gag protein of human immunodeficiency virus type 1. J Virol 77:1772–1783PubMedCrossRefGoogle Scholar
  34. Lin L, Goldberg YP, Ganz T (2005) Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 106:2884–2889PubMedCrossRefGoogle Scholar
  35. Ludbrook SB, Barry ST, Delves CJ, Horgan CM (2003) The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3. Biochem J 369:311–318PubMedCrossRefGoogle Scholar
  36. Main AL, Harvey TS, Baron M, Boyd J, Campbell ID (1992) The three-dimensional structure of the tenth type III module of fibronectin: an insight into RGD-mediated interactions. Cell 71:671–678PubMedCrossRefGoogle Scholar
  37. Matsunaga E, Chedotal A (2004) Repulsive guidance molecule/neogenin: a novel ligand-receptor system playing multiple roles in neural development. Dev Growth Differ 46:481–486PubMedCrossRefGoogle Scholar
  38. Mayer KM, McCorkle SR, Shanklin J (2005) Linking enzyme sequence to function using Conserved Property Difference Locator to identify and annotate positions likely to control specific functionality. BMC Bioinformatics 6:284PubMedCrossRefGoogle Scholar
  39. Monnier PP, Sierra A, Macchi P, Deitinghoff L, Andersen JS, Mann M, Flad M, Hornberger MR, Stahl B, Bonhoeffer F, Mueller BK (2002) RGM is a repulsive guidance molecule for retinal axons. Nature 419:392–395PubMedCrossRefGoogle Scholar
  40. Muller BK, Jay DG, Bonhoeffer F (1996) Chromophore-assisted laser inactivation of a repulsive axonal guidance molecule. Curr Biol 6:1497–1502PubMedCrossRefGoogle Scholar
  41. Nederbragt AJ, van Loon AE, Dictus WJ (2002) Expression of Patella vulgata orthologs of engrailed and dpp-BMP2/4 in adjacent domains during molluscan shell development suggests a conserved compartment boundary mechanism. Dev Biol 246:341–355PubMedCrossRefGoogle Scholar
  42. Nicholas K, Nicholas HJ, Deerfield DI (1997) GeneDoc: analysis and visualization of genetic variation. EMBNEW NEWS 4:14Google Scholar
  43. Niederkofler V, Salie R, Sigrist M, Arber S (2004) Repulsive guidance molecule (RGM) gene function is required for neural tube closure but not retinal topography in the mouse visual system. J Neurosci 24:808–818PubMedCrossRefGoogle Scholar
  44. Niederkofler V, Salie R, Arber S (2005) Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 115:2180–2186PubMedCrossRefGoogle Scholar
  45. Oldekamp J, Kramer N, Alvarez-Bolado G, Skutella T (2004) Expression pattern of the repulsive guidance molecules RGM A, B and C during mouse development. Gene Expr Patterns 4:283–288PubMedCrossRefGoogle Scholar
  46. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36:77–82PubMedCrossRefGoogle Scholar
  47. Peterson NA, Anderson BF, Jameson GB, Tweedie JW, Baker EN (2000) Crystal structure and iron-binding properties of the R210K mutant of the N-lobe of human lactoferrin: implications for iron release from transferrins. Biochemistry 39:6625–6633PubMedCrossRefGoogle Scholar
  48. Poirot O, O’Toole E, Notredame C (2003) Tcoffee@igs: A web server for computing, evaluating and combining multiple sequence alignments. Nucleic Acids Res 31:3503–3506PubMedCrossRefGoogle Scholar
  49. Puntervoll P, Linding R, Gemund C, Chabanis-Davidson S, Mattingsdal M, Cameron S, Martin DM, Ausiello G, Brannetti B, Costantini A, Ferre F, Maselli V, Via A, Cesareni G, Diella F, Superti-Furga G, Wyrwicz L, Ramu C, McGuigan C, Gudavalli R, Letunic I, Bork P, Rychlewski L, Kuster B, Helmer-Citterich M, Hunter WN, Aasland R, Gibson TJ (2003) ELM server: A new resource for investigating short functional sites in modular eukaryotic proteins. Nucleic Acids Res 31:3625–3630PubMedCrossRefGoogle Scholar
  50. Rajagopalan S, Deitinghoff L, Davis D, Conrad S, Skutella T, Chedotal A, Mueller BK, Strittmatter SM (2004) Neogenin mediates the action of repulsive guidance molecule. Nat Cell Biol 6:756–762PubMedCrossRefGoogle Scholar
  51. Rivard SR, Lanzara C, Grimard D, Carella M, Simard H, Ficarella R, Simard R, D’Adamo AP, Ferec C, Camaschella C, Mura C, Roetto A, De Braekeleer M, Bechner L, Gasparini P (2003) Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Eur J Hum Genet 11:585–589PubMedCrossRefGoogle Scholar
  52. Rodriguez A, Pan P, Parkkila S (2007) Expression studies of neogenin and its ligand hemojuvelin in mouse tissues. J Histochem Cytochem 55:85–96PubMedCrossRefGoogle Scholar
  53. Samad TA, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong SJ, Campagna JA, Perusini S, Fabrizio DA, Schneyer AL, Lin HY, Brivanlou AH, Attisano L, Woolf CJ (2005) DRAGON, a bone morphogenetic protein co-receptor. J Biol Chem 280:14122–14129PubMedCrossRefGoogle Scholar
  54. Samad TA, Srinivasan A, Karchewski LA, Jeong SJ, Campagna JA, Ji RR, Fabrizio DA, Zhang Y, Lin HY, Bell E, Woolf CJ (2004) DRAGON: a member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties. J Neurosci 24:2027–2036PubMedCrossRefGoogle Scholar
  55. Subramaniam S (1998) The Biology Workbench––a seamless database and analysis environment for the biologist. Proteins 32:1–2PubMedCrossRefGoogle Scholar
  56. Tajima F (1993) Simple methods for testing the molecular evolutionary clock hypothesis. Genetics 135:599–607PubMedGoogle Scholar
  57. Thompson J, Higgins D, Gibson T (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680PubMedCrossRefGoogle Scholar
  58. Waite KA, Eng C (2003) From developmental disorder to heritable cancer: it’s all in the BMP/TGF-beta family. Nat Rev Genet 4:763–773PubMedCrossRefGoogle Scholar
  59. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2:399–409PubMedCrossRefGoogle Scholar
  60. Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS (1997) Characterization of the CHD family of proteins. Proc Natl Acad Sci USA 94:11472–11477PubMedCrossRefGoogle Scholar
  61. Xia Y, Sidis Y, Mukherjee A, Samad TA, Brenner G, Woolf CJ, Lin HY, Schneyer A (2005) Localization and action of Dragon (repulsive guidance molecule b), a novel bone morphogenetic protein coreceptor, throughout the reproductive axis. Endocrinology 146:3614–3621PubMedCrossRefGoogle Scholar
  62. Zhang AS, West AP Jr, Wyman AE, Bjorkman PJ, Enn CA (2005) Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem 280:33885–33894PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of BiologyChatham UniversityPittsburghUSA

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