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An interrupted beta-propeller and protein disorder: structural bioinformatics insights into the N-terminus of alsin

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Abstract

Defects in the human ALS2 gene, which encodes the 1,657-amino-acid residue protein alsin, are linked to several related motor neuron diseases. We created a structural model for the N-terminal 690-residue region of alsin through comparative modelling based on regulator of chromosome condensation 1 (RCC1). We propose that this alsin region contains seven RCC1-like repeats in a seven-bladed beta-propeller structure. The propeller is formed by a double clasp arrangement containing two segments (residues 1–218 and residues 525–690). The 306-residue insert region, predicted to lie within blade 5 and to be largely disordered, is poorly conserved across species. Surface patches of evolutionary conservation probably indicate locations of binding sites. Both disease-causing missense mutations—Cys157Tyr and Gly540Glu—are buried in the propeller and likely to be structurally disruptive. This study aids design of experimental studies by highlighting the importance of construct length, will enhance interpretation of protein–protein interactions, and enable rational site-directed mutagenesis.

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References

  1. Brown RH Jr (1995) Cell 80:687–692. doi:10.1016/0092-8674(95)90346-1

    Article  CAS  Google Scholar 

  2. Devon RS, Schwab C, Topp JD, Orban PC, Yang YZ, Pape TD, Helm JR, Davidson TL, Rogers DA, Gros-Louis F, Rouleau G, Horazdovsky BF, Leavitt BR, Hayden MR (2005) Neurobiol Dis 18:243–257. doi:10.1016/j.nbd.2004.10.002

    Article  CAS  Google Scholar 

  3. Topp JD, Gray NW, Gerard RD, Horazdovsky BF (2004) J Biol Chem 279:24612–24623. doi:10.1074/jbc.M313504200

    Article  CAS  Google Scholar 

  4. Otomo A, Hadano S, Okada T, Mizumura H, Kunita R, Nishijima H, Showguchi-Miyata J, Yanagisawa Y, Kohiki E, Suga E, Yasuda M, Osuga H, Nishimoto T, Narumiya S, Ikeda JE (2003) Hum Mol Genet 12:1671–1687. doi:10.1093/hmg/ddg184

    Article  CAS  Google Scholar 

  5. Tudor EL, Perkinton MS, Schmidt A, Ackerley S, Brownlees J, Jacobsen NJ, Byers HL, Ward M, Hall A, Leigh PN, Shaw CE, McLoughlin DM, Miller CC (2005) J Biol Chem 280:34735–34740. doi:10.1074/jbc.M506216200

    Article  CAS  Google Scholar 

  6. Kanekura K, Hashimoto Y, Kita Y, Sasabe J, Aiso S, Nishimoto I, Matsuoka M (2005) J Biol Chem 280:4532–4543. doi:10.1074/jbc.M410508200

    Article  CAS  Google Scholar 

  7. Kunita R, Otomo A, Mizumura H, Suzuki-Utsunomiya K, Hadano S, Ikeda JE (2007) J Biol Chem 282:16599–16611. doi:10.1074/jbc.M610682200

    Article  CAS  Google Scholar 

  8. Panzeri C, De Palma C, Martinuzzi A, Daga A, De Polo G, Bresolin N, Miller CC, Tudor EL, Clementi E, Bassi MT (2006) Brain 129:1710–1719. doi:10.1093/brain/awl104

    Article  Google Scholar 

  9. Yamanaka K, Vande Velde C, Eymard-Pierre E, Bertini E, Boespflug-Tanguy O, Cleveland DW (2003) Proc Natl Acad Sci USA 100:16041–16046. doi:10.1073/pnas.2635267100

    Article  CAS  Google Scholar 

  10. Lai C, Xie C, McCormack SG, Chiang HC, Michalak MK, Lin X, Chandran J, Shim H, Shimoji M, Cookson MR, Huganir RL, Rothstein JD, Price DL, Wong PC, Martin LJ, Zhu JJ, Cai H (2006) J Neurosci 26:11798–11806. doi:10.1523/JNEUROSCI.2084-06.2006

    Article  CAS  Google Scholar 

  11. Renault L, Nassar N, Vetter I, Becker J, Klebe C, Roth M, Wittinghofer A (1998) Nature 392:97–101. doi:10.1038/32204

    Article  CAS  Google Scholar 

  12. Renault L, Kuhlmann J, Henkel A, Wittinghofer A (2001) Cell 105:245–255. doi:10.1016/S0092-8674(01)00315-4

    Article  CAS  Google Scholar 

  13. Pons T, Gomez R, Chinea G, Valencia A (2003) Curr Med Chem 10:505–524

    CAS  Google Scholar 

  14. Paoli M (2001) Prog Biophys Mol Biol 76:103–130. doi:10.1016/S0079-6107(01)00007-4

    Article  CAS  Google Scholar 

  15. Jawad Z, Paoli M (2002) Structure 10:447–454. doi:10.1016/S0969-2126(02)00750-5

    Article  CAS  Google Scholar 

  16. Murzin AG (1992) Proteins 14:191–201. doi:10.1002/prot.340140206

    Article  CAS  Google Scholar 

  17. Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE (2001) Nat Genet 29:166–173. doi:10.1038/ng1001-166

    Article  CAS  Google Scholar 

  18. Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE (2007) Neurochem Int 51:74–84. doi:10.1016/j.neuint.2007.04.010

    Article  CAS  Google Scholar 

  19. Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T (2001) Nat Genet 29:160–165. doi:10.1038/ng1001-160

    Article  CAS  Google Scholar 

  20. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) J Mol Biol 215:403–410

    CAS  Google Scholar 

  21. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Nucleic Acids Res 25:3389–3402. doi:10.1093/nar/25.17.3389

    Article  CAS  Google Scholar 

  22. Do CB, Mahabhashyam MS, Brudno M, Batzoglou S (2005) Genome Res 15:330–340. doi:10.1101/gr.2821705

    Article  CAS  Google Scholar 

  23. Jones DT (1999) J Mol Biol 292:195–202. doi:10.1006/jmbi.1999.3091

    Article  CAS  Google Scholar 

  24. McGuffin LJ, Bryson K, Jones DT (2000) Bioinformatics 16:404–405. doi:10.1093/bioinformatics/16.4.404

    Article  CAS  Google Scholar 

  25. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) Nucleic Acids Res 25:4876–4882. doi:10.1093/nar/25.24.4876

    Article  CAS  Google Scholar 

  26. Ginalski K, Elofsson A, Fischer D, Rychlewski L (2003) Bioinformatics 19:1015–1018. doi:10.1093/bioinformatics/btg124

    Article  CAS  Google Scholar 

  27. Kelley LA, MacCallum RM, Sternberg MJ (2000) J Mol Biol 299:499–520. doi:10.1006/jmbi.2000.3741

    Article  CAS  Google Scholar 

  28. Kabsch W, Sander C (1983) Biopolymers 22:2577–2637. doi:10.1002/bip.360221211

    Article  CAS  Google Scholar 

  29. Sali A, Blundell TL (1993) J Mol Biol 234:779–815. doi:10.1006/jmbi.1993.1626

    Article  CAS  Google Scholar 

  30. Laskowski RA, Macarthur MW, Moss DS, Thornton JM (1993) J Appl Cryst 26:283–291. doi:10.1107/S0021889892009944

    Article  CAS  Google Scholar 

  31. Bower MJ, Cohen FE, Dunbrack RL Jr (1997) J Mol Biol 267:1268–1282. doi:10.1006/jmbi.1997.0926

    Article  CAS  Google Scholar 

  32. Canutescu AA, Shelenkov AA, Dunbrack RL Jr (2003) Protein Sci 12:2001–2014. doi:10.1110/ps.03154503

    Article  CAS  Google Scholar 

  33. Vriend G, Sander C (1993) J Appl Cryst 26:47–60. doi:10.1107/S0021889892008240

    Article  CAS  Google Scholar 

  34. Vriend G (1990) J Mol Graph 8:52–56. doi:10.1016/0263-7855(90)80070-V

    Article  CAS  Google Scholar 

  35. Wallner B, Elofsson A (2003) Protein Sci 12:1073–1086. doi:10.1110/ps.0236803

    Article  CAS  Google Scholar 

  36. Pawlowski M, Gajda MJ, Matlak R, Bujnicki JM (2008) BMC Bioinformatics 9:403

    Article  Google Scholar 

  37. Fraczkiewicz R, Braun W (1998) J Comput Chem 19:319–333. doi:10.1002/(SICI)1096-987X(199802)19:3<319::AID-JCC6>3.0.CO;2-W

    Article  CAS  Google Scholar 

  38. Nicholls A, Sharp KA, Honig B (1991) Proteins 11:281–296. doi:10.1002/prot.340110407

    Article  CAS  Google Scholar 

  39. Linding R, Jensen LJ, Diella F, Bork P, Gibson TJ, Russell RB (2003) Structure 11:1453–1459. doi:10.1016/j.str.2003.10.002

    Article  CAS  Google Scholar 

  40. Obradovic Z, Peng K, Vucetic S, Radivojac P, Dunker AK (2005) Proteins 61(Suppl 7):176–182. doi:10.1002/prot.20735

    Article  CAS  Google Scholar 

  41. Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) BMC Bioinformatics 7:208. doi:10.1186/1471-2105-7-208

    Article  Google Scholar 

  42. Prilusky J, Felder CE, Zeev-Ben-Mordehai T, Rydberg EH, Man O, Beckmann JS, Silman I, Sussman JL (2005) Bioinformatics 21:3435–3438. doi:10.1093/bioinformatics/bti537

    Article  CAS  Google Scholar 

  43. Coeytaux K, Poupon A (2005) Bioinformatics 21:1891–1900. doi:10.1093/bioinformatics/bti266

    Article  CAS  Google Scholar 

  44. Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Proteins 42:38–48. doi:10.1002/1097-0134(20010101)42:1<38::AID-PROT50>3.0.CO;2-3

    Article  CAS  Google Scholar 

  45. Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) J Mol Biol 337:635–645. doi:10.1016/j.jmb.2004.02.002

    Article  CAS  Google Scholar 

  46. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 28:235–242. doi:10.1093/nar/28.1.235

    Article  CAS  Google Scholar 

  47. Sengupta J, Nilsson J, Gursky R, Spahn CM, Nissen P, Frank J (2004) Nat Struct Mol Biol 11:957–962. doi:10.1038/nsmb822

    Article  CAS  Google Scholar 

  48. Rakotobe D, Violot S, Hong SS, Gouet P, Boulanger P (2008) Virol J 5:32. doi:10.1186/1743-422X-5-32

    Article  Google Scholar 

  49. Gaudermann P, Vogl I, Zientz E, Silva FJ, Moya A, Gross R, Dandekar T (2006) BMC Microbiol 6:1. doi:10.1186/1471-2180-6-1

    Article  Google Scholar 

  50. Durand A, Villard C, Giardina T, Perrier J, Juge N, Puigserver A (2003) J Protein Chem 22:183–191. doi:10.1023/A:1023431215558

    Article  CAS  Google Scholar 

  51. Gifford ML, Robertson FC, Soares DC, Ingram GC (2005) Plant Cell 17:1154–1166. doi:10.1105/tpc.104.029975

    Article  CAS  Google Scholar 

  52. Oxvig C, Springer TA (1998) Proc Natl Acad Sci USA 95:4870–4875. doi:10.1073/pnas.95.9.4870

    Article  CAS  Google Scholar 

  53. Neer EJ, Smith TF (1996) Cell 84:175–178. doi:10.1016/S0092-8674(00)80969-1

    Article  CAS  Google Scholar 

  54. Lim D, Park HU, De Castro L, Kang SG, Lee HS, Jensen S, Lee KJ, Strynadka NC (2001) Nat Struct Biol 8:848–852. doi:10.1038/nsb1001-848

    Article  CAS  Google Scholar 

  55. Stevens TJ, Paoli M (2008) Proteins 70:378–387. doi:10.1002/prot.21521

    Article  CAS  Google Scholar 

  56. Appleton BA, Wu P, Wiesmann C (2006) Structure 14:87–96. doi:10.1016/j.str.2005.09.013

    Article  CAS  Google Scholar 

  57. Hadjebi O, Casas-Terradellas E, Garcia-Gonzalo FR, Rosa JL (2008) Biochim Biophys Acta 1783:1467–1479. doi:10.1016/j.bbamcr.2008.03.015

    Article  CAS  Google Scholar 

  58. Boeckmann B, Bairoch A, Apweiler R, Blatter MC, Estreicher A, Gasteiger E, Martin MJ, Michoud K, O’Donovan C, Phan I, Pilbout S, Schneider M (2003) Nucleic Acids Res 31:365–370. doi:10.1093/nar/gkg095

    Article  CAS  Google Scholar 

  59. Hadano S, Benn SC, Kakuta S, Otomo A, Sudo K, Kunita R, Suzuki-Utsunomiya K, Mizumura H, Shefner JM, Cox GA, Iwakura Y, Brown RH Jr, Ikeda JE (2006) Hum Mol Genet 15:233–250. doi:10.1093/hmg/ddi440

    Article  CAS  Google Scholar 

  60. Yamanaka K, Miller TM, McAlonis-Downes M, Chun SJ, Cleveland DW (2006) Ann Neurol 60:95–104. doi:10.1002/ana.20888

    Article  CAS  Google Scholar 

  61. Chaudhuri I, Soding J, Lupas AN (2008) Proteins 71:795–803. doi:10.1002/prot.21764

    Article  CAS  Google Scholar 

  62. Hsieh TJ, Farh L, Huang WM, Chan NL (2004) J Biol Chem 279:55587–55593. doi:10.1074/jbc.M408934200

    Article  CAS  Google Scholar 

  63. Hadano S, Otomo A, Suzuki-Utsunomiya K, Kunita R, Yanagisawa Y, Showguchi-Miyata J, Mizumura H, Ikeda JE (2004) FEBS Lett 575:64–70. doi:10.1016/j.febslet.2004.07.092

    Article  CAS  Google Scholar 

  64. Juhasz T, Szeltner Z, Fulop V, Polgar L (2005) J Mol Biol 346:907–917. doi:10.1016/j.jmb.2004.12.014

    Article  CAS  Google Scholar 

  65. Gregory DS, Martin AC, Cheetham JC, Rees AR (1993) Protein Eng 6:29–35. doi:10.1093/protein/6.1.29

    Article  CAS  Google Scholar 

  66. Lin CT, Lin KL, Yang CH, Chung IF, Huang CD, Yang YS (2005) Int J Neural Syst 15:71–84. doi:10.1142/S0129065705000116

    Article  Google Scholar 

  67. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Nature 362:59–62. doi:10.1038/362059a0

    Article  CAS  Google Scholar 

  68. Hart PJ, Liu H, Pellegrini M, Nersissian AM, Gralla EB, Valentine JS, Eisenberg D (1998) Protein Sci 7:545–555

    CAS  Google Scholar 

  69. Lyons TJ, Liu H, Goto JJ, Nersissian A, Roe JA, Graden JA, Cafe C, Ellerby LM, Bredesen DE, Gralla EB, Valentine JS (1996) Proc Natl Acad Sci USA 93:12240–12244. doi:10.1073/pnas.93.22.12240

    Article  CAS  Google Scholar 

  70. James PA, Talbot K (2006) Biochim Biophys Acta 1762:986–1000

    CAS  Google Scholar 

  71. Kanekura K, Hashimoto Y, Niikura T, Aiso S, Matsuoka M, Nishimoto I (2004) J Biol Chem 279:19247–19256. doi:10.1074/jbc.M313236200

    Article  CAS  Google Scholar 

  72. Oyanagi K, Kawakami E, Kikuchi-Horie K, Ohara K, Ogata K, Takahama S, Wada M, Kihira T, Yasui M (2006) Neuropathology 26:115–128. doi:10.1111/j.1440-1789.2006.00672.x

    Article  Google Scholar 

  73. Divers TJ, Cummings JE, de Lahunta A, Hintz HF, Mohammed HO (2006) Am J Vet Res 67:120–126. doi:10.2460/ajvr.67.1.120

    Article  CAS  Google Scholar 

  74. Ermilova IP, Ermilov VB, Levy M, Ho E, Pereira C, Beckman JS (2005) Neurosci Lett 379:42–46. doi:10.1016/j.neulet.2004.12.045

    Article  CAS  Google Scholar 

  75. Kihira T, Yoshida S, Yase Y, Ono S, Kondo T (2002) Neuropathology 22:171–179. doi:10.1046/j.1440-1789.2002.00441.x

    Article  Google Scholar 

  76. Kihira T, Yoshida S, Kondo T, Yase Y, Ono S (2004) J Neurol Sci 219:7–14. doi:10.1016/j.jns.2003.11.010

    Article  CAS  Google Scholar 

  77. Mallick P, Boutz DR, Eisenberg D, Yeates TO (2002) Proc Natl Acad Sci USA 99:9679–9684. doi:10.1073/pnas.142310499

    Article  CAS  Google Scholar 

  78. Fulop V, Jones DT (1999) Curr Opin Struct Biol 9:715–721. doi:10.1016/S0959-440X(99)00035-4

    Article  CAS  Google Scholar 

  79. Strange RW, Antonyuk S, Hough MA, Doucette PA, Rodriguez JA, Hart PJ, Hayward LJ, Valentine JS, Hasnain SS (2003) J Mol Biol 328:877–891. doi:10.1016/S0022-2836(03)00355-3

    Article  CAS  Google Scholar 

  80. Banci L, Bertini I, Cantini F, D’Amelio N, Gaggelli E (2006) J Biol Chem 281:2333–2337. doi:10.1074/jbc.M506497200

    Article  CAS  Google Scholar 

  81. Eymard-Pierre E, Yamanaka K, Haeussler M, Kress W, Gauthier-Barichard F, Combes P, Cleveland DW, Boespflug-Tanguy O (2006) Ann Neurol 59:976–980. doi:10.1002/ana.20879

    Article  CAS  Google Scholar 

  82. Hand CK, Devon RS, Gros-Louis F, Rochefort D, Khoris J, Meininger V, Bouchard JP, Camu W, Hayden MR, Rouleau GA (2003) Arch Neurol 60:1768–1771. doi:10.1001/archneur.60.12.1768

    Article  Google Scholar 

  83. Crennell S, Garman E, Laver G, Vimr E, Taylor G (1994) Structure 2:535–544. doi:10.1016/S0969-2126(00)00053-8

    Article  CAS  Google Scholar 

  84. Luo Y, Li SC, Chou MY, Li YT, Luo M (1998) Structure 6:521–530. doi:10.1016/S0969-2126(98)00053-7

    Article  CAS  Google Scholar 

  85. Springer TA (1997) Proc Natl Acad Sci USA 94:65–72. doi:10.1073/pnas.94.1.65

    Article  CAS  Google Scholar 

  86. Lu C, Oxvig C, Springer TA (1998) J Biol Chem 273:15138–15147. doi:10.1074/jbc.273.24.15138

    Article  CAS  Google Scholar 

  87. Aroul-Selvam R, Hubbard T, Sasidharan R (2004) J Mol Biol 338:633–641. doi:10.1016/j.jmb.2004.03.039

    Article  CAS  Google Scholar 

  88. Selvam RA, Sasidharan R (2004) Nucleic Acids Res 32:D193–D195. doi:10.1093/nar/gkh047

    Article  CAS  Google Scholar 

  89. Saini HK, Fischer D (2005) Bioinformatics 21:2917–2920. doi:10.1093/bioinformatics/bti445

    Article  CAS  Google Scholar 

  90. Fink AL (2005) Curr Opin Struct Biol 15:35–41. doi:10.1016/j.sbi.2005.01.002

    Article  CAS  Google Scholar 

  91. Iakoucheva LM, Radivojac P, Brown CJ, O’Connor TR, Sikes JG, Obradovic Z, Dunker AK (2004) Nucleic Acids Res 32:1037–1049. doi:10.1093/nar/gkh253

    Article  CAS  Google Scholar 

  92. Karlin D, Longhi S, Receveur V, Canard B (2002) Virology 296:251–262. doi:10.1006/viro.2001.1296

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Dr. Andrew F. Coulson for critical reading of the manuscript, and Dr. Alice J. Walmesley and Prof. Lindsay Sawyer for helpful discussions. D.C.S. acknowledges funding from a Strategic Research Development Grant. The model co-ordinates are available from D.C.S. upon request.

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Authors and Affiliations

  1. Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK

    Dinesh C. Soares, David J. Porteous & Rebecca S. Devon

  2. School of Chemistry, University of Edinburgh, Joseph Black Building, Kings Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK

    Dinesh C. Soares & Paul N. Barlow

  3. Institute of Structural and Molecular Biology, University of Edinburgh, Michael Swann Building, Kings Buildings, Mayfield Road, Edinburgh, EH9 3JR, UK

    Paul N. Barlow

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  1. Dinesh C. Soares
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Soares, D.C., Barlow, P.N., Porteous, D.J. et al. An interrupted beta-propeller and protein disorder: structural bioinformatics insights into the N-terminus of alsin. J Mol Model 15, 113–122 (2009). https://doi.org/10.1007/s00894-008-0381-1

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