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. 1986 Jun;5(6):1335–1342. doi: 10.1002/j.1460-2075.1986.tb04364.x

Mitochondrial targeting sequences may form amphiphilic helices.

G von Heijne
PMCID: PMC1166945  PMID: 3015599

Abstract

Twenty three mitochondrial targeting sequences have been analysed with regard to their potential for forming amphiphilic helices. It is shown that most if not all of these sequences can be expected to form helices with high hydrophobic moments in a suitable environment. In the few cases studied so far, the segments of maximal hydrophobic moment coincide closely with 'critical' regions defined by deletions and point mutations.

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Selected References

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  1. Boutry M., Chua N. H. A nuclear gene encoding the beta subunit of the mitochondrial ATP synthase in Nicotiana plumbaginifolia. EMBO J. 1985 Sep;4(9):2159–2165. doi: 10.1002/j.1460-2075.1985.tb03910.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chothia C., Levitt M., Richardson D. Structure of proteins: packing of alpha-helices and pleated sheets. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4130–4134. doi: 10.1073/pnas.74.10.4130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chou P. Y., Fasman G. D. Empirical predictions of protein conformation. Annu Rev Biochem. 1978;47:251–276. doi: 10.1146/annurev.bi.47.070178.001343. [DOI] [PubMed] [Google Scholar]
  4. De Haan M., van Loon A. P., Kreike J., Vaessen R. T., Grivell L. A. The biosynthesis of the ubiquinol-cytochrome c reductase complex in yeast. DNA sequence analysis of the nuclear gene coding for the 14-kDa subunit. Eur J Biochem. 1984 Jan 2;138(1):169–177. doi: 10.1111/j.1432-1033.1984.tb07896.x. [DOI] [PubMed] [Google Scholar]
  5. Eisenberg D., Schwarz E., Komaromy M., Wall R. Analysis of membrane and surface protein sequences with the hydrophobic moment plot. J Mol Biol. 1984 Oct 15;179(1):125–142. doi: 10.1016/0022-2836(84)90309-7. [DOI] [PubMed] [Google Scholar]
  6. Eisenberg D., Weiss R. M., Terwilliger T. C. The hydrophobic moment detects periodicity in protein hydrophobicity. Proc Natl Acad Sci U S A. 1984 Jan;81(1):140–144. doi: 10.1073/pnas.81.1.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Faye G., Simon M. Analysis of a yeast nuclear gene involved in the maturation of mitochondrial pre-messenger RNA of the cytochrome oxidase subunit I. Cell. 1983 Jan;32(1):77–87. doi: 10.1016/0092-8674(83)90498-1. [DOI] [PubMed] [Google Scholar]
  8. Flinta C., Persson B., Jörnvall H., von Heijne G. Sequence determinants of cytosolic N-terminal protein processing. Eur J Biochem. 1986 Jan 2;154(1):193–196. doi: 10.1111/j.1432-1033.1986.tb09378.x. [DOI] [PubMed] [Google Scholar]
  9. Flinta C., von Heijne G., Johansson J. Helical sidedness and the distribution of polar residues in trans-membrane helices. J Mol Biol. 1983 Jul 25;168(1):193–196. doi: 10.1016/s0022-2836(83)80330-1. [DOI] [PubMed] [Google Scholar]
  10. Guiard B. Structure, expression and regulation of a nuclear gene encoding a mitochondrial protein: the yeast L(+)-lactate cytochrome c oxidoreductase (cytochrome b2). EMBO J. 1985 Dec 1;4(12):3265–3272. doi: 10.1002/j.1460-2075.1985.tb04076.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Harnisch U., Weiss H., Sebald W. The primary structure of the iron-sulfur subunit of ubiquinol-cytochrome c reductase from Neurospora, determined by cDNA and gene sequencing. Eur J Biochem. 1985 May 15;149(1):95–99. doi: 10.1111/j.1432-1033.1985.tb08898.x. [DOI] [PubMed] [Google Scholar]
  12. Hase T., Müller U., Riezman H., Schatz G. A 70-kd protein of the yeast mitochondrial outer membrane is targeted and anchored via its extreme amino terminus. EMBO J. 1984 Dec 20;3(13):3157–3164. doi: 10.1002/j.1460-2075.1984.tb02274.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hase T., Riezman H., Suda K., Schatz G. Import of proteins into mitochondria: nucleotide sequence of the gene for a 70-kd protein of the yeast mitochondrial outer membrane. EMBO J. 1983;2(12):2169–2172. doi: 10.1002/j.1460-2075.1983.tb01718.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hay R., Böhni P., Gasser S. How mitochondria import proteins. Biochim Biophys Acta. 1984 Jan 27;779(1):65–87. doi: 10.1016/0304-4157(84)90004-2. [DOI] [PubMed] [Google Scholar]
  15. Hennig B., Neupert W. Assembly of cytochrome c. Apocytochrome c is bound to specific sites on mitochondria before its conversion to holocytochrome c. Eur J Biochem. 1981 Dec;121(1):203–212. doi: 10.1111/j.1432-1033.1981.tb06450.x. [DOI] [PubMed] [Google Scholar]
  16. Hol W. G. The role of the alpha-helix dipole in protein function and structure. Prog Biophys Mol Biol. 1985;45(3):149–195. doi: 10.1016/0079-6107(85)90001-x. [DOI] [PubMed] [Google Scholar]
  17. Horwich A. L., Fenton W. A., Williams K. R., Kalousek F., Kraus J. P., Doolittle R. F., Konigsberg W., Rosenberg L. E. Structure and expression of a complementary DNA for the nuclear coded precursor of human mitochondrial ornithine transcarbamylase. Science. 1984 Jun 8;224(4653):1068–1074. doi: 10.1126/science.6372096. [DOI] [PubMed] [Google Scholar]
  18. Horwich A. L., Kalousek F., Fenton W. A., Pollock R. A., Rosenberg L. E. Targeting of pre-ornithine transcarbamylase to mitochondria: definition of critical regions and residues in the leader peptide. Cell. 1986 Feb 14;44(3):451–459. doi: 10.1016/0092-8674(86)90466-6. [DOI] [PubMed] [Google Scholar]
  19. Hurt E. C., Müller U., Schatz G. The first twelve amino acids of a yeast mitochondrial outer membrane protein can direct a nuclear-coded cytochrome oxidase subunit to the mitochondrial inner membrane. EMBO J. 1985 Dec 16;4(13A):3509–3518. doi: 10.1002/j.1460-2075.1985.tb04110.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hurt E. C., Pesold-Hurt B., Suda K., Oppliger W., Schatz G. The first twelve amino acids (less than half of the pre-sequence) of an imported mitochondrial protein can direct mouse cytosolic dihydrofolate reductase into the yeast mitochondrial matrix. EMBO J. 1985 Aug;4(8):2061–2068. doi: 10.1002/j.1460-2075.1985.tb03892.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ito A., Ogishima T., Ou W., Omura T., Aoyagi H., Lee S., Mihara H., Izumiya N. Effects of synthetic model peptides resembling the extension peptides of mitochondrial enzyme precursors on import of the precursors into mitochondria. J Biochem. 1985 Dec;98(6):1571–1582. doi: 10.1093/oxfordjournals.jbchem.a135426. [DOI] [PubMed] [Google Scholar]
  22. Janin J., Chothia C. Packing of alpha-helices onto beta-pleated sheets and the anatomy of alpha/beta proteins. J Mol Biol. 1980 Oct 15;143(1):95–128. doi: 10.1016/0022-2836(80)90126-6. [DOI] [PubMed] [Google Scholar]
  23. Jay G., Nomura S., Anderson C. W., Khoury G. Identification of the SV40 agnogene product: a DNA binding protein. Nature. 1981 May 28;291(5813):346–349. doi: 10.1038/291346a0. [DOI] [PubMed] [Google Scholar]
  24. Joh T., Nomiyama H., Maeda S., Shimada K., Morino Y. Cloning and sequence analysis of a cDNA encoding porcine mitochondrial aspartate aminotransferase precursor. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6065–6069. doi: 10.1073/pnas.82.18.6065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kaiser E. T., Kézdy F. J. Amphiphilic secondary structure: design of peptide hormones. Science. 1984 Jan 20;223(4633):249–255. doi: 10.1126/science.6322295. [DOI] [PubMed] [Google Scholar]
  26. Kanellis P., Romans A. Y., Johnson B. J., Kercret H., Chiovetti R., Jr, Allen T. M., Segrest J. P. Studies of synthetic peptide analogs of the amphipathic helix. Effect of charged amino acid residue topography on lipid affinity. J Biol Chem. 1980 Dec 10;255(23):11464–11472. [PubMed] [Google Scholar]
  27. Kaput J., Goltz S., Blobel G. Nucleotide sequence of the yeast nuclear gene for cytochrome c peroxidase precursor. Functional implications of the pre sequence for protein transport into mitochondria. J Biol Chem. 1982 Dec 25;257(24):15054–15058. [PubMed] [Google Scholar]
  28. Kempf C., Klausner R. D., Weinstein J. N., Van Renswoude J., Pincus M., Blumenthal R. Voltage-dependent trans-bilayer orientation of melittin. J Biol Chem. 1982 Mar 10;257(5):2469–2476. [PubMed] [Google Scholar]
  29. Lau S. H., Rivier J., Vale W., Kaiser E. T., Kézdy F. J. Surface properties of an amphiphilic peptide hormone and of its analog: corticotropin-releasing factor and sauvagine. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7070–7074. doi: 10.1073/pnas.80.23.7070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lomax M. I., Bachman N. J., Nasoff M. S., Caruthers M. H., Grossman L. I. Isolation and characterization of a cDNA clone for bovine cytochrome c oxidase subunit IV. Proc Natl Acad Sci U S A. 1984 Oct;81(20):6295–6299. doi: 10.1073/pnas.81.20.6295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Maarse A. C., Van Loon A. P., Riezman H., Gregor I., Schatz G., Grivell L. A. Subunit IV of yeast cytochrome c oxidase: cloning and nucleotide sequencing of the gene and partial amino acid sequencing of the mature protein. EMBO J. 1984 Dec 1;3(12):2831–2837. doi: 10.1002/j.1460-2075.1984.tb02216.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Marres C. A., Van Loon A. P., Oudshoorn P., Van Steeg H., Grivell L. A., Slater E. C. Nucleotide sequence analysis of the nuclear gene coding for manganese superoxide dismutase of yeast mitochondria, a gene previously assumed to code for the Rieske iron-sulphur protein. Eur J Biochem. 1985 Feb 15;147(1):153–161. doi: 10.1111/j.1432-1033.1985.tb08731.x. [DOI] [PubMed] [Google Scholar]
  33. McIntyre P., Graf L., Mercer J., Peterson G., Hudson P., Hoogenraad N. A highly basic N-terminal extension of the mitochondrial matrix enzyme ornithine transcarbamylase from rat liver. FEBS Lett. 1984 Nov 5;177(1):41–46. doi: 10.1016/0014-5793(84)80977-1. [DOI] [PubMed] [Google Scholar]
  34. Mihara K., Sato R. Molecular cloning and sequencing of cDNA for yeast porin, an outer mitochondrial membrane protein: a search for targeting signal in the primary structure. EMBO J. 1985 Mar;4(3):769–774. doi: 10.1002/j.1460-2075.1985.tb03695.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Moe G. R., Kaiser E. T. Design, synthesis, and characterization of a model peptide having potent calcitonin-like biological activity: implications for calcitonin structure/activity. Biochemistry. 1985 Apr 9;24(8):1971–1976. doi: 10.1021/bi00329a026. [DOI] [PubMed] [Google Scholar]
  36. Morohashi K., Fujii-Kuriyama Y., Okada Y., Sogawa K., Hirose T., Inayama S., Omura T. Molecular cloning and nucleotide sequence of cDNA for mRNA of mitochondrial cytochrome P-450(SCC) of bovine adrenal cortex. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4647–4651. doi: 10.1073/pnas.81.15.4647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nagata S., Tsunetsugu-Yokota Y., Naito A., Kaziro Y. Molecular cloning and sequence determination of the nuclear gene coding for mitochondrial elongation factor Tu of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6192–6196. doi: 10.1073/pnas.80.20.6192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nyunoya H., Broglie K. E., Widgren E. E., Lusty C. J. Characterization and derivation of the gene coding for mitochondrial carbamyl phosphate synthetase I of rat. J Biol Chem. 1985 Aug 5;260(16):9346–9356. [PubMed] [Google Scholar]
  39. Okamura T., John M. E., Zuber M. X., Simpson E. R., Waterman M. R. Molecular cloning and amino acid sequence of the precursor form of bovine adrenodoxin: evidence for a previously unidentified COOH-terminal peptide. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5705–5709. doi: 10.1073/pnas.82.17.5705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pfanner N., Neupert W. Transport of proteins into mitochondria: a potassium diffusion potential is able to drive the import of ADP/ATP carrier. EMBO J. 1985 Nov;4(11):2819–2825. doi: 10.1002/j.1460-2075.1985.tb04009.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Roise D., Horvath S. J., Tomich J. M., Richards J. H., Schatz G. A chemically synthesized pre-sequence of an imported mitochondrial protein can form an amphiphilic helix and perturb natural and artificial phospholipid bilayers. EMBO J. 1986 Jun;5(6):1327–1334. doi: 10.1002/j.1460-2075.1986.tb04363.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sadler I., Suda K., Schatz G., Kaudewitz F., Haid A. Sequencing of the nuclear gene for the yeast cytochrome c1 precursor reveals an unusually complex amino-terminal presequence. EMBO J. 1984 Sep;3(9):2137–2143. doi: 10.1002/j.1460-2075.1984.tb02103.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schleyer M., Neupert W. Transport of proteins into mitochondria: translocational intermediates spanning contact sites between outer and inner membranes. Cell. 1985 Nov;43(1):339–350. doi: 10.1016/0092-8674(85)90039-x. [DOI] [PubMed] [Google Scholar]
  44. Smith M., Leung D. W., Gillam S., Astell C. R., Montgomery D. L., Hall B. D. Sequence of the gene for iso-1-cytochrome c in Saccharomyces cerevisiae. Cell. 1979 Apr;16(4):753–761. doi: 10.1016/0092-8674(79)90091-6. [DOI] [PubMed] [Google Scholar]
  45. Suissa M., Suda K., Schatz G. Isolation of the nuclear yeast genes for citrate synthase and fifteen other mitochondrial proteins by a new screening method. EMBO J. 1984 Aug;3(8):1773–1781. doi: 10.1002/j.1460-2075.1984.tb02045.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sundaralingam M., Drendel W., Greaser M. Stabilization of the long central helix of troponin C by intrahelical salt bridges between charged amino acid side chains. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7944–7947. doi: 10.1073/pnas.82.23.7944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Séraphin B., Simon M., Faye G. Primary structure of a gene for subunit V of the cytochrome c oxidase from Saccharomyces cerevisiae. Curr Genet. 1985;9(6):435–439. doi: 10.1007/BF00434047. [DOI] [PubMed] [Google Scholar]
  48. Terwilliger T. C., Eisenberg D. The structure of melittin. II. Interpretation of the structure. J Biol Chem. 1982 Jun 10;257(11):6016–6022. [PubMed] [Google Scholar]
  49. Van Loon A. P., De Groot R. J., De Haan M., Dekker A., Grivell L. A. The DNA sequence of the nuclear gene coding for the 17-kd subunit VI of the yeast ubiquinol-cytochrome c reductase: a protein with an extremely high content of acidic amino acids. EMBO J. 1984 May;3(5):1039–1043. doi: 10.1002/j.1460-2075.1984.tb01924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Viebrock A., Perz A., Sebald W. The imported preprotein of the proteolipid subunit of the mitochondrial ATP synthase from Neurospora crassa. Molecular cloning and sequencing of the mRNA. EMBO J. 1982;1(5):565–571. doi: 10.1002/j.1460-2075.1982.tb01209.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wright R. M., Ko C., Cumsky M. G., Poyton R. O. Isolation and sequence of the structural gene for cytochrome c oxidase subunit VI from Saccharomyces cerevisiae. J Biol Chem. 1984 Dec 25;259(24):15401–15407. [PubMed] [Google Scholar]
  52. Young E. T., Pilgrim D. Isolation and DNA sequence of ADH3, a nuclear gene encoding the mitochondrial isozyme of alcohol dehydrogenase in Saccharomyces cerevisiae. Mol Cell Biol. 1985 Nov;5(11):3024–3034. doi: 10.1128/mcb.5.11.3024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. von Heijne G. Signal sequences. The limits of variation. J Mol Biol. 1985 Jul 5;184(1):99–105. doi: 10.1016/0022-2836(85)90046-4. [DOI] [PubMed] [Google Scholar]

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