Biotechnology Letters

, Volume 28, Issue 24, pp 1971–1982

Protein biosensors based on the principle of fluorescence resonance energy transfer for monitoring cellular dynamics

Review

Abstract

Genetically-coded, fluorescence resonance energy transfer (FRET) biosensors are widely used to study molecular events from single cells to whole organisms. They are unique among biosensors because of their spontaneous fluorescence and targeting specificity to both organelles and tissues. In this review, we discuss the theoretical basis of FRET with a focus on key parameters responsible for designing FRET biosensors that have the highest sensitivity. Next, we discuss recent applications that are grouped into four common biosensor design patterns—intermolecular FRET, intramolecular FRET, FRET from substrate cleavage and FRET using multiple colour fluorescent proteins. Lastly, we discuss recent progress in creating fluorescent proteins suitable for FRET purposes. Together these advances in the development of FRET biosensors are beginning to unravel the interconnected and intricate signalling processes as they are occurring in living cells and organisms.

Keywords

Fluorescence resonance energy transfer (FRET) Genetically coded biosensor Green fluorescent protein (GFP) Intermolecular FRET Intramolecular FRET Protein conformational changes Protein–substrate interaction Substrate cleavage Transgenic organisms 

References

  1. Azpiazu I, Gautam N (2004) A fluorescence resonance energy transfer-based sensor indicates that receptor access to a G protein is unrestricted in a living mammalian cell. J Biol Chem 279(26):27709–27718PubMedCrossRefGoogle Scholar
  2. Bevis BJ, Glick BS (2002) Rapidly maturing variants of the Discosoma red fluorescent protein (DsRed). Nat Biotechnol 20(1):83–87PubMedCrossRefGoogle Scholar
  3. Braun DC, Garfield SH, Blumberg PM (2005) Analysis by fluorescence resonance energy transfer of the interaction between ligands and protein kinase Cdelta in the intact cell. J Biol Chem 280(9):8164–8171PubMedCrossRefGoogle Scholar
  4. Camuzeaux B, Spriet C, Heliot L, Coll J, Duterque-Coquillaud M (2005) Imaging Erg and Jun transcription factor interaction in living cells using fluorescence resonance energy transfer analyses. Biochem Biophys Res Commun 332(4):1107–1114PubMedCrossRefGoogle Scholar
  5. Chiang JJ, Truong K (2005) Using co-cultures expressing fluorescence resonance energy transfer based protein biosensors to simultaneously image caspase-3 and Ca2+ signaling. Biotechnol Lett 27(16):1219–1227PubMedCrossRefGoogle Scholar
  6. De S, Macara IG, Lannigan DA (2005) Novel biosensors for the detection of estrogen receptor ligands. J Steroid Biochem Mol Biol 96(3–4):235–244PubMedCrossRefGoogle Scholar
  7. Diegelmann S, Fiala A, Leibold C, Spall T, Buchner E (2002) Transgenic flies expressing the fluorescence calcium sensor Cameleon 2.1 under UAS control. Genesis 34(1–2):95–98PubMedCrossRefGoogle Scholar
  8. Endoh T, Funabashi H, Mie M, Kobatake E (2005) Method for detection of specific nucleic acids by recombinant protein with fluorescent resonance energy transfer. Anal Chem 77(14):4308–4314PubMedCrossRefGoogle Scholar
  9. Fehr M, Frommer WB, Lalonde S (2002) Visualization of maltose uptake in living yeast cells by fluorescent nanosensors. Proc Natl Acad Sci USA 99(15):9846–9851PubMedCrossRefGoogle Scholar
  10. Fehr M, Lalonde S, Ehrhardt DW, Frommer WB (2004) Live imaging of glucose homeostasis in nuclei of COS-7 cells. J Fluoresc 14(5):603–609PubMedCrossRefGoogle Scholar
  11. Fehr M, Lalonde S, Lager I, Wolff MW, Frommer WB (2003) In vivo imaging of the dynamics of glucose uptake in the cytosol of COS-7 cells by fluorescent nanosensors. J Biol Chem 278(21):19127–19133PubMedCrossRefGoogle Scholar
  12. Fiala A, Spall T (2003) In vivo calcium imaging of brain activity in Drosophila by transgenic cameleon expression. Sci STKE 2003(174):PL6PubMedGoogle Scholar
  13. Fiala A, Spall T, Diegelmann S, Eisermann B, Sachse S, Devaud JM, Buchner E, Galizia CG (2002) Genetically expressed cameleon in Drosophila melanogaster is used to visualize olfactory information in projection neurons. Curr Biol 12(21):1877–1884PubMedCrossRefGoogle Scholar
  14. Galperin E, Verkhusha VV, Sorkin A (2004) Three-chromophore FRET microscopy to analyze multiprotein interactions in living cells. Nat Meth 1(3):209–217CrossRefGoogle Scholar
  15. Griesbeck O, Baird GS, Campbell RE, Zacharias DA, Tsien RY (2001) Reducing the environmental sensitivity of yellow fluorescent protein. Mechanism and applications. J Biol Chem 276(31):29188–29194PubMedCrossRefGoogle Scholar
  16. Hara M, Bindokas V, Lopez JP, Kaihara K, Landa LR Jr, Harbeck M, Roe MW (2004) Imaging endoplasmic reticulum calcium with a fluorescent biosensor in transgenic mice. Am J Physiol Cell Physiol 287(4):C932–C938PubMedCrossRefGoogle Scholar
  17. He L, Wu X, Simone J, Hewgill D, Lipsky PE (2005) Determination of tumor necrosis factor receptor-associated factor trimerization in living cells by CFP→YFP→mRFP FRET detected by flow cytometry. Nucleic Acids Res 33(6):e61PubMedCrossRefGoogle Scholar
  18. Higashijima S, Masino MA, Mandel G, Fetcho JR (2003) Imaging neuronal activity during zebrafish behavior with a genetically encoded calcium indicator. J Neurophysiol 90(6):3986–3997PubMedCrossRefGoogle Scholar
  19. Itoh RE, Kurokawa K, Ohba Y, Yoshizaki H, Mochizuki N, Matsuda M (2002) Activation of rac and cdc42 video imaged by fluorescent resonance energy transfer-based single-molecule probes in the membrane of living cells. Mol Cell Biol 22(18):6582–6591PubMedCrossRefGoogle Scholar
  20. Jones J, Heim R, Hare E, Stack J, Pollok BA (2000) Development and application of a GFP-FRET intracellular caspase assay for drug screening. J Biomol Screen 5(5):307–318PubMedCrossRefGoogle Scholar
  21. Karasawa S, Araki T, Nagai T, Mizuno H, Miyawaki A (2004) Cyan-emitting and orange-emitting fluorescent proteins as a donor/acceptor pair for fluorescence resonance energy transfer. Biochem J 381(Pt 1):307–312PubMedGoogle Scholar
  22. Kerr R, Lev-Ram V, Baird G, Vincent P, Tsien RY, Schafer WR (2000) Optical imaging of calcium transients in neurons and pharyngeal muscle of C. elegans. Neuron 26(3):583–594PubMedCrossRefGoogle Scholar
  23. Kramer JM, Yi L, Shen F, Maitra A, Jiao X, Jin T, Gaffen SL (2006) Evidence for ligand-independent multimerization of the IL-17 receptor. J Immunol 176(2):711–715PubMedGoogle Scholar
  24. Lissandron V, Terrin A, Collini M, D’Alfonso L, Chirico G, Pantano S, Zaccolo M (2005) Improvement of a FRET-based indicator for cAMP by linker design and stabilization of donor-acceptor interaction. J Mol Biol 354(3):546–555PubMedCrossRefGoogle Scholar
  25. Luo KQ, Yu VC, Pu Y, Chang DC (2003) Measuring dynamics of caspase-8 activation in a single living HeLa cell during TNFalpha-induced apoptosis. Biochem Biophys Res Commun 304(2):217–222PubMedCrossRefGoogle Scholar
  26. Mank M, Reiff DF, Heim N, Friedrich MW, Borst A, Griesbeck O (2006) A FRET-based calcium biosensor with fast signal kinetics and high fluorescence change. Biophys J 90(5):1790–1796PubMedCrossRefGoogle Scholar
  27. Mitra RD, Silva CM, Youvan DC (1996) Fluorescence resonance energy transfer between blue-emitting and red-shifted excitation derivatives of the green fluorescent protein. Gene 173(1 Spec No):13–17PubMedCrossRefGoogle Scholar
  28. Miyawaki A, Griesbeck O, Heim R, Tsien RY (1999) Dynamic and quantitative Ca2+ measurements using improved cameleons. Proc Natl Acad Sci USA 96(5):2135–2140PubMedCrossRefGoogle Scholar
  29. Miyawaki A, Llopis J, Heim R, McCaffery JM, Adams JA, Ikura M, Tsien RY (1997) Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature 388(6645):882–887PubMedCrossRefGoogle Scholar
  30. Nagai T, Ibata K, Park ES, Kubota M, Mikoshiba K, Miyawaki A (2002) A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nat Biotechnol 20(1):87–90PubMedCrossRefGoogle Scholar
  31. Nagai T, Miyawaki A (2004) A high-throughput method for development of FRET-based indicators for proteolysis. Biochem Biophys Res Commun 319(1):72–77PubMedCrossRefGoogle Scholar
  32. Nagai T, Yamada S, Tominaga T, Ichikawa M, Miyawaki A (2004) Expanded dynamic range of fluorescent indicators for Ca(2+) by circularly permuted yellow fluorescent proteins. Proc Natl Acad Sci USA 101(29):10554–10559PubMedCrossRefGoogle Scholar
  33. Nguyen AW, Daugherty PS (2005) Evolutionary optimization of fluorescent proteins for intracellular FRET. Nat Biotechnol 23(3):355–360PubMedCrossRefGoogle Scholar
  34. Nikolaev VO, Gambaryan S, Lohse MJ (2006) Fluorescent sensors for rapid monitoring of intracellular cGMP. Nat Meth 3(1):23–25CrossRefGoogle Scholar
  35. Nyqvist D, Mattsson G, Kohler M, Lev-Ram V, Andersson A, Carlsson PO, Nordin A, Berggren PO, Jansson L (2005) Pancreatic islet function in a transgenic mouse expressing fluorescent protein. J Endocrinol 186(2):333–341PubMedCrossRefGoogle Scholar
  36. Okumoto S, Looger LL, Micheva KD, Reimer RJ, Smith SJ, Frommer WB (2005) Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors. Proc Natl Acad Sci USA 102(24):8740–8745PubMedCrossRefGoogle Scholar
  37. Onuki R, Nagasaki A, Kawasaki H, Baba T, Uyeda TQ, Taira K (2002) Confirmation by FRET in individual living cells of the absence of significant amyloid beta -mediated caspase 8 activation. Proc Natl Acad Sci USA 99(23):14716–14721PubMedCrossRefGoogle Scholar
  38. Osibow K, Malli R, Kostner GM, Graier WF (2006) A new type of non-Ca2+-buffering Apo(a)-based fluorescent indicator for intraluminal Ca2+ in the endoplasmic reticulum. J Biol Chem 281(8):5017–5025PubMedCrossRefGoogle Scholar
  39. Pedelacq JD, Cabantous S, Tran T, Terwilliger TC, Waldo GS (2006) Engineering and characterization of a superfolder green fluorescent protein. Nat Biotechnol 24(1):79–88PubMedCrossRefGoogle Scholar
  40. Remus TP, Zima AV, Bossuyt J, Bare DJ, Martin JL, Blatter LA, Bers DM, Mignery GA (2006) Biosensors to measure inositol 1,4,5-trisphosphate concentration in living cells with spatiotemporal resolution. J Biol Chem 281(1):608–616PubMedCrossRefGoogle Scholar
  41. Rizzo MA, Springer GH, Granada B, Piston DW (2004) An improved cyan fluorescent protein variant useful for FRET. Nat Biotechnol 22(4):445–449PubMedCrossRefGoogle Scholar
  42. Rudolf R, Mongillo M, Magalhaes PJ, Pozzan T (2004) In vivo monitoring of Ca(2+) uptake into mitochondria of mouse skeletal muscle during contraction. J Cell Biol 166(4):527–536PubMedCrossRefGoogle Scholar
  43. Sakai R, Repunte-Canonigo V, Raj CD, Knopfel T (2001) Design and characterization of a DNA-encoded, voltage-sensitive fluorescent protein. Eur J Neurosci 13(12):2314–2318PubMedCrossRefGoogle Scholar
  44. Sato M, Ozawa T, Inukai K, Asano T, Umezawa Y (2002) Fluorescent indicators for imaging protein phosphorylation in single living cells. Nat Biotechnol 20(3):287–294PubMedCrossRefGoogle Scholar
  45. Sato M, Umezawa Y (2004) Imaging protein phosphorylation by fluorescence in single living cells. Methods 32(4):451–455PubMedCrossRefGoogle Scholar
  46. Schleifenbaum A, Stier G, Gasch A, Sattler M, Schultz C (2004) Genetically encoded FRET probe for PKC activity based on pleckstrin. J Am Chem Soc 126(38):11786–11787PubMedCrossRefGoogle Scholar
  47. Seth A, Otomo T, Yin HL, Rosen MK (2003) Rational design of genetically encoded fluorescence resonance energy transfer-based sensors of cellular Cdc42 signaling. Biochemistry 42(14):3997–4008PubMedCrossRefGoogle Scholar
  48. Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY (2004) Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol 22(12):1567–1572PubMedCrossRefGoogle Scholar
  49. Shaner NC, Steinbach PA, Tsien RY (2005) A guide to choosing fluorescent proteins. Nat Meth 2(12):905–909CrossRefGoogle Scholar
  50. Steinmeyer R, Noskov A, Krasel C, Weber I, Dees C, Harms GS (2005) Improved fluorescent proteins for single-molecule research in molecular tracking and co-localization. J Fluoresc 15(5):707–721PubMedCrossRefGoogle Scholar
  51. Stockholm D, Bartoli M, Sillon G, Bourg N, Davoust J, Richard I (2005) Imaging calpain protease activity by multiphoton FRET in living mice. J Mol Biol 346(1):215–222PubMedCrossRefGoogle Scholar
  52. Tanimura A, Nezu A, Morita T, Turner RJ, Tojyo Y (2004) Fluorescent biosensor for quantitative real-time measurements of inositol 1,4,5-trisphosphate in single living cells. J Biol Chem 279(37):38095–38098PubMedCrossRefGoogle Scholar
  53. Ting AY, Kain KH, Klemke RL, Tsien RY (2001) Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells. Proc Natl Acad Sci USA 98(26):15003–15008PubMedCrossRefGoogle Scholar
  54. Truong K, Sawano A, Mizuno H, Hama H, Tong KI, Mal TK, Miyawaki A, Ikura M (2001) FRET-based in vivo Ca2+ imaging by a new calmodulin-GFP fusion molecule. Nat Struct Biol 8(12):1069–1073PubMedCrossRefGoogle Scholar
  55. Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T (2005) Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor. J Neurosci 25(32):7459–7469PubMedCrossRefGoogle Scholar
  56. Valeur B (2002). Molecular fluorescence: principles and applications. Wiley-VCH, WeinheimGoogle Scholar
  57. Wang Y, Botvinick EL, Zhao Y, Berns MW, Usami S, Tsien RY, Chien S (2005) Visualizing the mechanical activation of Src. Nature 434(7036):1040–1045PubMedCrossRefGoogle Scholar
  58. Xu X, Gerard AL, Huang BC, Anderson DC, Payan DG, Luo Y (1998) Detection of programmed cell death using fluorescence energy transfer. Nucleic Acids Res 26(8):2034–2035PubMedCrossRefGoogle Scholar
  59. Yamada A, Hirose K, Hashimoto A, Iino M (2005) Real-time imaging of myosin II regulatory light-chain phosphorylation using a new protein biosensor. Biochem J 385(Pt 2):589–594PubMedGoogle Scholar
  60. Yang X, Xu P, Xu T (2005) A new pair for inter- and intra-molecular FRET measurement. Biochem Biophys Res Commun 330(3):914–920PubMedCrossRefGoogle Scholar
  61. Ye K, Schultz JS (2003) Genetic engineering of an allosterically based glucose indicator protein for continuous glucose monitoring by fluorescence resonance energy transfer. Anal Chem 75(14):3451–3459PubMedCrossRefGoogle Scholar
  62. Zaccolo M, Cesetti T, Di Benedetto G, Mongillo M, Lissandron V, Terrin A, Zamparo I (2005) Imaging the cAMP-dependent signal transduction pathway. Biochem Soc Trans 33(Pt 6):1323–1326PubMedGoogle Scholar
  63. Zaccolo M, Magalhaes P, Pozzan T (2002) Compartmentalisation of cAMP and Ca(2+) signals. Curr Opin Cell Biol 14(2):160–166PubMedCrossRefGoogle Scholar
  64. Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295(5560):1711–1715PubMedCrossRefGoogle Scholar
  65. Zapata-Hommer O, Griesbeck O (2003) Efficiently folding and circularly permuted variants of the Sapphire mutant of GFP. BMC Biotechnol 3:5PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Institute of Biomaterials and Biomedical EngineeringUniversity of TorontoTorontoCanada
  2. 2.Edward S. Rogers Sr. Department of Electrical and Computer EngineeringUniversity of TorontoTorontoCanada

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