The CFTR-derived peptides as a model of sequence-specific protein aggregation

• Autorzy: Bak D , Cutting G.R. , Milewski M.
• Języki publikacji: EN

Abstrakty

EN

Protein aggregation is a hallmark of a growing group of pathologies known as conformational diseases. Although many native or mutated proteins are able to form aggregates, the exact amino acid sequences involved in the process of aggregation are known only in a few cases. Hence, there is a need for different model systems to expand our knowledge in this area. The so-called ag region was previously found to cause the aggregation of the C-terminal fragment of the cystic fibrosis transmembrane conductance regulator (CFTR). To investigate whether this specific amino acid sequence is able to induce protein aggregation irrespective of the amino acid context, we altered its position within the CFTR-derived C-terminal peptide and analyzed the localization of such modified peptides in transfected mammalian cells. Insertion of the ag region into a different amino acid background affected not only the overall level of intracellular protein aggregation, but also the morphology and subcellular localization of aggregates, suggesting that sequences other than the ag region can substantially influence the peptide’s behavior. Also, the introduction of a short dipeptide (His-Arg) motif, a crucial component of the ag region, into different locations within the C-terminus of CFTR lead to changes in the aggregation pattern that were less striking, although still statistically significant. Thus, our results indicate that even subtle alterations within the aggregating peptide can affect many different aspects of the aggregation process.

Słowa kluczowe

EN

green fluorescent protein; site-directed mutagenesis; conformational disease; cystic fibrosis transmembrane conductance regulator; protein aggregation; pathology

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2007
• Tom: 12
• Numer: 3
• Opis fizyczny: p.435-447,fig.,ref.

Twórcy

autor

Bak D

• Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland

autor

Cutting G.R.

autor

Milewski M.

Bibliografia

• 1. Carrell, R.W. and Lomas, D.A. Conformational disease. Lancet 350 (1997) 134-138.
• 2. Kisilevsky, R. and Fraser, P.E. A beta amyloidogenesis: unique, or variation on a systemic theme? Crit. Rev. Biochem. Mol. Biol. 32 (1997) 361-404.
• 3. Kopito, R.R. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10 (2000) 524-530.
• 4. Donaldson, K.M., Li, W., Ching, K.A., Batalov, S., Tsai, C.C. and Joazeiro C.A. Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc. Natl. Acad. Sci. USA 100 (2003) 8892- 8897.
• 5. Kazantsev, A., Preisinger, E., Dranovsky, A., Goldgaber, D. and Housman, D. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc. Natl. Acad. Sci. USA 96 (1999) 11404-11409.
• 6. Preisinger, E., Jordan, B.M., Kazantsev, A. and Housman, D. Evidence for a recruitment and sequestration mechanism in Huntington's disease. Philos. Trans. R. Soc. Lond B Biol. Sci. 354 (1999) 1029-1034.
• 7. Schaffar, G., Breuer, P., Boteva, R., Behrends, C., Tzvetkov, N., Strippel, N., Sakahira, H., Siegers, K., Hayer-Hartl, M. and Hartl, F.U. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol. Cell. 15 (2004) 95-105.
• 8. Suhr, S.T., Senut, M.C., Whitelegge, J.P., Faull, K.F., Cuizon, D.B. and Gage, F.H. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J. Cell Biol. 153 (2001) 283-294.
• 9. Stenoien, D.L., Cummings, C.J., Adams, H.P., Mancini, M.G., Patel, K., DeMartino, G.N., Marcelli, M., Weigel, N.L. and Mancini, M.A. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum. Mol. Genet. 8 (1999) 731-741.
• 10. Chai, Y., Wu, L., Griffin, J.D. and Paulson, H.L. The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease. J. Biol. Chem. 276 (2001) 44889-44897.
• 11. Nozaki, K., Onodera, O., Takano, H. and Tsuji, S. Amino acid sequences flanking polyglutamine stretches influence their potential for aggregate formation. Neuroreport 12 (2001) 3357-3364.
• 12. DiFiglia, M. Huntingtin fragments that aggregate go their separate ways. Mol. Cell. 10 (2002) 224-225.
• 13. Ziegler, J., Viehrig, C., Geimer, S., Rosch, P. and Schwarzinger, S. Putative aggregation initiation sites in prion protein. FEBS Lett. 580 (2006) 2033- 2040.
• 14. Gautreau, A., Fievet, B.T., Brault, E., Antony, C., Houdusse, A., Louvard, D. and Arpin, M. Isolation and characterization of an aggresome determinant in the NF2 tumor suppressor. J. Biol. Chem. 278 (2003) 6235- 6242.
• 15. Link, C.D., Fonte, V., Hiester, B., Yerg, J., Ferguson, J., Csontos, S., Silverman, M.A. and Stein, G.H. Conversion of green fluorescent protein into a toxic, aggregation-prone protein by C-terminal addition of a short peptide. J. Biol. Chem. 281 (2006) 1808-1816.
• 16. Giasson, B.I., Murray, I.V., Trojanowski, J.Q. and Lee, V.M. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J. Biol. Chem. 276 (2001) 2380-2386.
• 17. Johnston, J.A., Ward, C.L. and Kopito, R.R. Aggresomes: a cellular response to misfolded proteins. J. Cell Biol. 143 (1998) 1883-1898.
• 18. Bence, N.F., Sampat, R.M. and Kopito, R.R. Impairment of the ubiquitinproteasome system by protein aggregation. Science 292 (2001) 1552-1555.
• 19. Rajan, R.S., Illing, M.E., Bence, N.F. and Kopito, R.R. Specificity in intracellular protein aggregation and inclusion body formation. Proc. Natl. Acad. Sci. USA 98 (2001) 13060-13065.
• 20. Corboy, M.J., Thomas, P.J. and Wigley, W.C. CFTR degradation and aggregation. Methods Mol. Med. 70 (2002) 277-294.
• 21. Mukai, H., Isagawa, T., Goyama, E., Tanaka, S., Bence, N.F., Tamura, A., Ono, Y. and Kopito, R.R. Formation of morphologically similar globular aggregates from diverse aggregation-prone proteins in mammalian cells. Proc. Natl. Acad. Sci. USA 102 (2005) 10887-10892.
• 22. Milewski, M.I., Mickle, J.E., Forrest, J.K., Stanton, B.A. and Cutting, G.R. Aggregation of misfolded proteins can be a selective process dependent upon peptide composition. J. Biol. Chem. 277 (2002) 34462-34470.
• 23. Milewski, M.I., Mickle, J.E., Forrest, J.K., Stafford, D.M., Moyer, B.D., Cheng, J., Guggino, W.B., Stanton, B.A. and Cutting, G.R. A PDZ-binding motif is essential but not sufficient to localize the C terminus of CFTR to the apical membrane. J. Cell Sci. 114 (2001) 719-726.
• 24. Zeitlin, P.L., Lu, L., Rhim, J., Cutting, G., Stetten, G., Kieffer, K.A., Craig, R. and Guggino, W.B. A cystic fibrosis bronchial epithelial cell line: immortalization by adeno-12-SV40 infection. Am. J. Respir. Cell Mol. Biol. 4 (1991) 313-319.
• 25. Jiang, X., Hill, W.G., Pilewski, J.M. and Weisz, O.A. Glycosylation differences between a cystic fibrosis and rescued airway cell line are not CFTR dependent. Am. J. Physiol. 273 (1997) L913-L920.
• 26. Eudes, R., Lehn, P., Ferec, C., Mornon, J.P. and Callebaut, I. Nucleotide binding domains of human CFTR: a structural classification of critical residues and disease-causing mutations. Cell Mol. Life Sci. 62 (2005) 2112- 2123.
• 27. Moyer, B.D., Duhaime, M., Shaw, C., Denton, J., Reynolds, D., Karlson, K.H., Pfeiffer, J., Wang, S., Mickle, J.E., Milewski, M., Cutting, G.R., Guggino, W.B., Li, M. and Stanton, B.A. The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane. J. Biol. Chem. 275 (2000) 27069-27074.
• 28. Thomas, C.L. and Maule, A.J. Limitations on the use of fused green fluorescent protein to investigate structure-function relationships for the cauliflower mosaic virus movement protein. J. Gen. Virol. 81 (2000) 1851- 1855.
• 29. Peters, M.F., Nucifora, F.C., Jr., Kushi, J., Seaman, H.C., Cooper, J.K., Herring, W.J., Dawson, V.L., Dawson, T.M. and Ross, C.A. Nuclear targeting of mutant Huntingtin increases toxicity. Mol. Cell Neurosci. 14 (1999) 121-128.
• 30. Gutekunst, C.A., Li, S.H., Yi, H., Mulroy, J.S., Kuemmerle, S., Jones, R., Rye, D., Ferrante, R.J., Hersch, S.M. and Li, X.J. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci. 19 (1999) 2522-2534.
• 31. Yang, W., Dunlap, J.R., Andrews, R.B. and Wetzel, R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum. Mol. Genet. 11 (2002) 2905-2917.
• 32. Schilling, G., Savonenko, A.V., Klevytska, A., Morton, J.L., Tucker, S.M., Poirier, M., Gale, A., Chan, N., Gonzales, V., Slunt, H.H., Coonfield, M.L., Jenkins, N.A., Copeland, N.G., Ross, C.A. and Borchelt, D.R. Nucleartargeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. Hum. Mol. Genet. 13 (2004) 1599-1610.
• 33. Duennwald, M.L., Jagadish, S., Muchowski, P.J. and Lindquist, S. Flanking sequences profoundly alter polyglutamine toxicity in yeast. Proc. Natl. Acad. Sci. USA 103 (2006) 11045-11050.