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Saposins and Their Interaction with Lipids

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Abstract

The lysosomal degradation of several sphingolipids requires the presence of four small glycoproteins called saposins, generated by proteolytic processing of a common precursor, prosaposin. Saposins share several structural properties, including six similarly located cysteines forming three disulfide bridges with the same cysteine pairings. Recently it has been noted that also other proteins have the same polypeptide motif characterized by the similar location of six cysteines. These saposin-like (SAPLIP) proteins are surfactant protein B (SP-B), ‘Entamoeba histolytica’ poreforming peptide, NK-lysin, acid sphingomyelinase and acyloxyacyl hydrolase. The structural homology and the conserved disulfide bridges suggest for all SAPLIPs a common fold, called ‘saposin fold’. Up to now a precise fold, comprising five α-helices, has been established only for NK-lysin. Despite their similar structure each saposin promotes the degradation of specific sphingolipids in lysosomes, e.g. Sap B that of sulfatides and Sap C that of glucosylceramides. The different activities of the saposins must reside within the module of the α-helices and/or in additional specific regions of the molecule. It has been reported that saposins bind to lysosomal hydrolases and to several sphingolipids. Their structural and functional properties have been extensively reviewed and hypotheses regarding their molecular mechanisms of action have been proposed. Recent work of our group has evidenced a novel property of saposins: some of them undergo an acid-induced change in hydrophobicity that triggers their binding to phospholipid membranes. In this article we shortly review recent findings on the structure of saposins and on their interactions with lipids, with special attention to interactions with phospholipids. These findings offer a new approach for understanding the physiological role of saposins in lysosomes.

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REFERENCES

  1. O'Brien, J., and Kishimoto, Y. 1991. Saposin proteins: structure, function, and role in human lysosomal storage disorders. FASEB J. 5:301–308.

    PubMed  Google Scholar 

  2. Kishimoto, Y., Hiraiwa, M., and O'Brien, J. S. 1992. Saposins: structure, function distribution, and molecular genetics. J. Lipid Res. 33:1255–1267.

    PubMed  Google Scholar 

  3. Furst, W., and Sandhoff, K. 1992. Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim. Biophys. Acta 1126:1–16.

    PubMed  Google Scholar 

  4. Sandhoff, K., Harzer, K., and Furst, W. 1995. Sphingolipid activator proteins. Pages 2427–2441. In Seriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D., (eds) The Metabolic and Molecular Bases of Inherited disease. McGraw-Hill, Book Co., New York.

    Google Scholar 

  5. Munford, R.S., Sheppard, P.O., and O'Hara, P.J. 1995. Saposin-like proteins (SAPLIP) carry out diverse functions on a common backbone structure. J. Lipid Res. 36:1653–1663.

    PubMed  Google Scholar 

  6. Suzuki, K. 1995. Sphingolipid activator proteins. Pages 25–37, in Apps, D.K., and Tipton, K.F. (eds.) Essays in Biochemistry, Vol. 29, Academic Press.

  7. Vielhaber, G., Hurwitz, R., and Sandhoff, K. 1996. Biosynthesis, processing, and targeting of sphingolipid activator protein (Sap) precursor in cultured human fibroblasts. J. Biol. Chem. 271:32438–32446.

    PubMed  Google Scholar 

  8. Schnabel, D., Schroder, M., Furst, W., Klein, A., Hurwitz, R., Zenk, T., Weber, J., Harzer, K., Paton, B.C., Poulos, A., Suzuki, K., and Sandhoff, K. 1992. Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene. J. Biol. Chem. 267, 3312–3315.

    PubMed  Google Scholar 

  9. Bradova, V., Smid, F., Ulrich-Bott, B., Roggendorf, W., Paton, B.C., and Harzer, K. 1993. Prosaposin deficiency: further chacterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and storage disease. Hum. Genet. 92, 143–152.

    PubMed  Google Scholar 

  10. Wenger, D.A., De Gala, G., Williams, C., Taylor, H.A., Stevenson, R.E., Pruitt, J.R., Miller, J., Garen, P.D. and Balentine, J.D. 1989. Clinical, pathological, and biochemical studies on an infantile case of sulfatide/GM1 activator protein deficiency. Am. J. Med. Genet. 33:255–265.

    PubMed  Google Scholar 

  11. Schlote, W., Harzer, K., Christomanou, H., Paton, B.C., Kustermann-Kuhn, B., Schmid, B., Seeger, J., Bendt, U., Schuster, I., and Langenbeck, U. 1991. Sphingolipid activator protein 1 deficiency in metachromatic leukodystrophy with normal arylsulfatase A activity. A clinical, morphological, biochemical and immunological study. Eur. J. Pediatr. 150:584–591.

    PubMed  Google Scholar 

  12. Christomanou, H., Chabas, A., Pampols, T., and Guardiola, A. 1989. Activator protein deficient Gaucher's disease Klin. Wochenschr. 67:999–1003.

    Google Scholar 

  13. Morimoto, S., Martin, B.M., Yamamoto, Y., Kretz, K.A., O'Brien, J.S., and Kishimoto, Y. 1989. Saposin A: second cerebrosidase activator protein. Proc. Natl. Acad. Sci. USA, 86, 3389–3393.

    PubMed  Google Scholar 

  14. Vaccaro, A.M., Tatti, M., Ciaffoni, F., Salvioli, R., Barca, A., and Scerch C. 1995. Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide. J. Biol. Chem. 272:16862–16867.

    Google Scholar 

  15. Klein, A., Henseler, M., Klein, C., Suzuki, K., Harzer, K., and Sandhoff, K. 1994. Sphingolipid activator protein D (sap-D) stimulates the lysosomal degradation of ceramide ‘in vivo’. Biochem. Biophys. Res. Commun. 200:1440–1448.

    PubMed  Google Scholar 

  16. Johansson, J., Curstedt, T., and Jornvall, H. 1991. Surfactant protein B: disulfide bridges, structural properties, and kringle similarities. Biochemistry 30:6917–6921.

    PubMed  Google Scholar 

  17. Zaltash, S. and Johansson, J. 1998. Secondary structure and limited proteolysis give experimental evidence that the precursor of pulmonary surfactant protein B contains three saposin-like domains FEBS Lett 423:1–4.

    PubMed  Google Scholar 

  18. Lynch, E.C., Rosenberg, I.M., and Gitler, C. 1982. An ion-channel forming protein produced by Entamoeba histolytica. EMBO J., 1:801–804.

    PubMed  Google Scholar 

  19. Leippe, M., Tannich, E., Nickel, R., van der Goot, G., Pattus, F., Horstmann, R.D., and Muller-Eberhard, H.J. 1992. Primary and secondary structure of the pore-forming peptide of pathogenic Entamoeba histolytica. EMBO J. 11:3501–3506.

    PubMed  Google Scholar 

  20. Andersson, M. Gunne, H., Agerberth, B., Boman, A., Bergman, T., Sillard, R., Jornvall, H., Mutt, V., Olsson, B., Wigzell, H., Dagerlind, A., Boman, H.G., and Gudmundsson, G.H. 1995. NK-lysin, a novel effector peptide of cytotoxic T and NK cells. Structure and cDNA cloning of the porcine form, induction by interleukin 2, antibacterial and antitumor activity. EMBO J. 14:1615–1625.

    PubMed  Google Scholar 

  21. Ponting, C.P. 1994. Acid sphingomyelinase possesses a domain homologous to its activator proteins: saposins B and D. Protein Sci. 3:359–361.

    PubMed  Google Scholar 

  22. Hagen, F.S., Grant, F.J., Kuijper, J.L., Slaughter, C.A., Moomaw, C.R., Orth, K., O'Hara, P.J., and Munford R.S. 1991. Expression and characterization of recombinant human acyloxyacyl hydrolase, a leukocyte enzyme that deacylates bacterial lipopolysac-charides. Biochemistry. 30:8415–8423.

    PubMed  Google Scholar 

  23. Ponting, C.P., and Russell, R.B. 1995. Swaposins: circular permutations within genes encoding saposin homologues. TIBS 20:179–180.

    PubMed  Google Scholar 

  24. Guruprasad, K., Tormakangas, K., Kervinen, J., and Blundell, T.L. 1994. Comparative modelling of barley-grain aspartic proteinase: a structural rationale for observed hydrolytic specificity. FEBS Lett., 352:131–136.

    PubMed  Google Scholar 

  25. Vaccaro, A.M., Salvioli, R., Barca, A., Tatti, M., Ciaffoni, F., Maras, B., Siciliano, R., Zappacosta, F., Amoresano, A., and Pucci, P. 1995. Structural analysis of saposin C and B: complete localization of disulfide bridges. J. Biol. Chem. 270:9953–9960.

    PubMed  Google Scholar 

  26. Liepinsh, E., Andersson, M., Ruysschaert, J.M., and Otting, G. 1997. Saposin fold revealed by the NMR structure of NK-lysin. Nature Struct. Biol., 4:793–795.

    PubMed  Google Scholar 

  27. Andersson, M., Hilmgren, A., and Spyrou, G. 1996. NK-lysin, a disulfide-containing effector peptide of T-lymphocytes, is reduced and inactivated by human thioredoxin reductase: implication for a protective mechanism against NK-lysin cytotoxicity. J. Biol. Chem. 271:10116–10120.

    PubMed  Google Scholar 

  28. Vaccaro, A.M., Ciaffoni, F., Tatti, M Salvioli, R., Barca, A., Tognozzi, D., and Scerch, C. 1995. PH-dependent conformational properties of saposins and their interactions with phospholipid membranes. J. Biol. Chem. 270:30576–30580.

    PubMed  Google Scholar 

  29. Sanchez-Ferrer, A., Bru, R., and Garcia-Carmona, F. 1994. Phase separation of biomolecules in polyoxyethylene glycol nonionic detergents. Crit. Rev. Biochem. Mol. Biol. 29:275–313.

    PubMed  Google Scholar 

  30. Fricker, L.D., Das, B and Hogue Angeletti, R. 1990. Identification of the pH-dependent membrane anchor of Carboxypeptidase (EC 3.4.17.10). J. Biol. Chem., 265, 2476–2482.

    PubMed  Google Scholar 

  31. Escuyer, V., Boquet, P., Perrin, D., Montecucco, C., and Mock, M. 1986. A pH-induced increase in hydrophobicity as a possible step in the penetration of colicin E3 through bacterial membranes. J. Biol. Chem. 261:10891–10898.

    PubMed  Google Scholar 

  32. Doms, R.W., White, J., Boulay, F., and Helenius, A. 1990. Influenza virus hemagglutinin and membrane fusion. Pages 313–335, in Wilschut, J. and Hoekstra, D. (Eds.), Membrane Fusion, Marcel Dekker, Inc., New York.

    Google Scholar 

  33. Wilschut, J. 1990. Membrane fusion in lipid vesicle systems. Pages 89–126, in Wilschut, J. and Hoekstra, D. (Eds.), Membrane Fusion, Marcel Dekker, Inc., New York.

    Google Scholar 

  34. Willemsen, R., van Dongen, J.M., Ginns, E.I., Sips, H.J., Schram, A.W., Tager, J.M., Barranger, J.A., and Reuser, A.J.J. 1987. Ultrastructural localization of glucocerebrosidase in cultured Gaucher's fibroblasts by immunocytochemistry. J. Neurol., 234:44–51.

    PubMed  Google Scholar 

  35. Vaccaro, A.M., Tatti, M., Ciaffoni, F., Salvioli, R., Barca, A., and Roncaioli, P. 1993. Studies on glucosylceramidase binding to phosphatidylserine liposomes: the role of bilayer curvature. Biochim. Biophys. Acta 1149:55–62.

    PubMed  Google Scholar 

  36. Vaccaro, A.M., Tatti, M., Ciaffoni, F., Salvioli, R., and Roncaioli, P. 1992. Reconstitution of glucosylceramidase on binding to acidic phospholipid-containing vesicles. Biochim. Biophys. Acta, 1119:239–246.

    PubMed  Google Scholar 

  37. Vaccaro, A.M., Tatti, M., Ciaffoni, F., Salvioli, R., Maras, B., and Barca, A. 1993. Function of saposin C in the reconstitution of glucosylceramidase by phosphatidylserine liposomes. FEBS Lett. 336:159–162.

    PubMed  Google Scholar 

  38. Thompson, T.E., Allietta, M., Brown, R.E., Johnson, M.L., and Tillak, T.W. 1985. Organization of ganglioside GM1 in phosphatidylcholine bilayers. Biochim. Biophys. Acta, 817:229–237.

    PubMed  Google Scholar 

  39. Rock, P., Allietta, M., Young, W.W., Jr., Thompson, T.E., and Tillak, T.W. 1990. Organization of glycosphingolipids in phosphatidylcholine bilayers: use of antbody molecules and Fab fragments as morphologic markers. Biochemistry 29:8484–8490.

    PubMed  Google Scholar 

  40. Hiraiwa, M., Soeda, S., Kishimoto, Y., and O'Brien, J. S. 1992. Binding and transport of gangliosides by prosaposin. Proc. Natl. Acad. Sci. USA, 89:11254–11258.

    PubMed  Google Scholar 

  41. Vogel, A., Schwarzmann, G. and Sandhoff, K. 1991. Glycosphingolipid specificity of the human sulfatide ativator protein. Eur. J. Biochem. 200:591–597.

    PubMed  Google Scholar 

  42. Soeda, S., Hiraiwa, M., O'Brien, J.S., and Kishimoto, Y. 1993. Binding of cerebrosides and sulfatides to saposins A-D. J. Biol. Chem. 268:18519–18523.

    PubMed  Google Scholar 

  43. Azuma, N., O'Brien, J., Moser, H.W., and Kishimoto, Y. 1994. Stimulation of acid ceramidase activity by saposin D. Archiv. Biochem. Biophys. 311:354–357.

    Google Scholar 

  44. Morimoto, S., Kishimoto, Y., Tomich, J., Weiler, S., Ohashi, T., Barranger, J. A., Kretz, K.A., and O'Brien, J. S. 1990. Interactions of saposins, acidic lipids, and glucosylceramidase J. Biol. Chem. 265, 1933–1937.

    PubMed  Google Scholar 

  45. Shiffer, K., Hawgood, S., Duzgunes, N., and Goerke, J. 1988. Interactions of the low molecular weight group of surfactant-associated proteins (SP 5–18) with pulmonary surfactant lipids. Biochemistry, 27:2689–2695.

    PubMed  Google Scholar 

  46. Baatz, J.E., Elledge, B., and Whitsett, J.A. 1990. Surfactant protein SP-B induces ordering at the surface of model membrane bilayers. Biochemistry, 29:6714–6720.

    PubMed  Google Scholar 

  47. Longo, M.L., Bisagno, A.M., Zasadzinski, J.A., Bruni, R., and Waring, A.J. 1993. A function of lung surfactant protein SP-B. Science, 261:453–456.

    PubMed  Google Scholar 

  48. Leippe M., Ebel S., Schoenberger O.L., Horstmann, R.D. and Muller-Eberhard, H.J. 1991. Pore-forming peptide of pathogenic Entamoeba histolytica. Proc. Natl. Acad. Sci. USA, 88:7659–7663.

    PubMed  Google Scholar 

  49. Sixl, F., Brophy, P.J., and Watts, A. 1984. Selective protein-lipid interactions at membrane surfaces: a deuterium and phosphorus nuclear magnetic resonance study of the association of myelin basic protein with the bilayer head groups of dimyristoylphosphatidylcholine and dimyristoylphosphatidyl glycerol. Biochemistry 23:2032–2039.

    Google Scholar 

  50. Yang, L., and Glaser, M. 1995. Membrane domains containing phosphatidylserine and substrate can be important for the activation of protein kinase C. Biochemistry, 34:1500–1506.

    PubMed  Google Scholar 

  51. van Klompenburg, W., Nilsson, I., von Heijne, G., and de Kruiff, B. 1997. Anionic phospholipids are determinants of membrane protein topology. EMBO J. 16:4261–4266.

    PubMed  Google Scholar 

  52. Holtzman, E. 1989. Acidification; Membrane properties; Permeability and transport. Pages 93–160, in Lysosomes, Plenum Press, New York.

    Google Scholar 

  53. Li, S.C., Kihara, H., Serizawa, S., Li, Y.T., Fluharty, A.L., Mayes, J.S., and Shapiro, L.J. 1985. Activator protein required for the enzymatic hydrolysis of cerebroside sulfate. J. Biol. Chem. 260:1867–1871.

    PubMed  Google Scholar 

  54. Fabbro, D., and Grabowski, G.A. 1991. Human acid β-glucosydase. Use of imhibitory and activating monoclonal antibodies to investigate the enzym's catalytic mechanism and saposin A and C binding sites. J. Biol. Chem. 266:15021–15027.

    PubMed  Google Scholar 

  55. Qi, X., Leonova, T., and Grabowski, G.A. 1994. Functional human saposins expressed in Escherichia coli. Evidence for binding and activation properties of saposins C with acid β-glucosydase. J. Biol. Chem. 269:16746–16753.

    PubMed  Google Scholar 

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  1. Department of Metabolism and Pathological Biochemistry, Istituto Superiore Sanita', Viale Regina Elena 299, 00161, Roma, Italy

    Anna Maria Vaccaro, Rosa Salvioli, Massimo Tatti & Fiorella Ciaffoni

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Vaccaro, A.M., Salvioli, R., Tatti, M. et al. Saposins and Their Interaction with Lipids. Neurochem Res 24, 307–314 (1999). https://doi.org/10.1023/A:1022530508763

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