The Bic Inhibitor Of Cry-Cry And Cry-Cib Oligomerization/ Clustering

Tech ID: 29918 / UC Case 2015-354-0

Summary

UCLA researchers in the Department of Molecular, Cell, and Developmental Biology have discovered two Arabidopsis proteins, BIC1 and BIC2, that are capable of inhibiting light-dependent dimerization of cryptochrome (CRY) molecules. These BICs can be used as an improved drug screening platform through controlled, titratable, label-free and reversible protein – protein interactions.

Background

Cryptochromes are blue-light receptors that are involved in photomorphogenesis in plants and are critical components of the human circadian clock, which is associated with numerous human diseases, including diabetes, obesity, cancer, mania etc. The Arabidopsis cryptochrome 2 (CRY2) undergoes blue light-dependent dimerization via disulfide bonds, resulting in activation of the photoreceptor necessary for light-dependent growth and reproduction. The light-dependent CRY2-CIB1 interaction has been utilized as an optogenetics tool to achieve light-induced regulation of transcription, protein translocation, DNA recombination, phosphoinositide metabolism, epigenetics change, and reversible protein inactivation trap in molecular mechanistic studies and drug discovery studies. The CRY2-CIB1 interaction also requires CRY2 dimerization. Therefore, a technology that can control CRY dimerization can be used as a regulator of CRY2-CIB1 interaction-dependent optogenetics tools, and most importantly, as a novel approach to regulate CRY and circadian clock activity in human cells in many disease models.

Innovation

Researchers at UCLA have discovered two Arabidopsis proteins, blue-light inhibitors of CRY1 and CRY2 (BIC1, BIC2), that inhibit light-dependent formation of disulfide bonds between CRY molecules, leading to the suppression of CRY dimerization, CRY phosphorylation, and all physiological functions of cryptochromes.  These Arabidopsis BICs not only function in plant cells- they also demonstrate activities in human cells.

Applications

  •  Biomedical researches and drug discovery:

- Regulators of any optogenetics method that relies on the light-dependent CRY2-CIB1 interaction

- Drug screening applications through titratable, label-free and reversible protein – protein interactions

- Regulators of CRY and circadian clock activity in human cells

 

  • Regulators of crop growth, reproduction, and yield

Advantages

  • BICs are the first proteins discovered to inhibit CRY dimerization and light-dependent CRY2-CIB1 interaction
  • Plant BICs directly inhibits dimerization of human CRYs in human cells provides a novel approach to regulate CRY and circadian clock activity in human cells with great specificity

State Of Development

  • Successful demonstration of Arabidopsis BICs inhibition of light-dependent dimerization of human cryptochromes in human embryo kidney cell line.

Patent Status

Patent Pending

Related Materials

  • Liu, H., Yu, X., Li, K., Klejnot, J., Yang, H., Lisiero, D., Lin, C. (2008) "Photoexcited CRY2 Interacts with CIB1 to Regulate Transcription and Floral Initiation in Arabidopsis" Science 322:1535 – 1539.
  • Yu, X., Sayegh, R., Maymon, M., Warpeha, K., Klejnot, J., Yang, H., Huang, J., Lee, J., Kaufman, L., and Lin, C. (2009) Formation of nuclear bodies of Arabidopsis CRY2 in response to blue light is associated with blue light-dependent degradation of the photoreceptor Plant Cell 21: 118130.
  • Yu, X., Liu, H., Klejnot, J., and Lin, C. (2010) The Cryptochrome Blue Light Receptors, The Arabidopsis Book 8:e0136. doi:10.1199/tab.0136
  • Li, X., Wang, Q., Yu, X., Liu, H., Yang, H., Zhao, C., Liu, X., Tan, C., Klejnot, J., Zhong, D., and Lin, C (2011) Arabidopsis CRY2 functions by the photoactivation mechanism distinct from the trp triad-dependent photoreduction Proc Natl Acad Sci U S A, 108:20844-20849
  • Zuo, Z., Meng, Y., Yu, W., Zhang, Z., Feng, D., Sun, S Liu, B., and Lin, C. (2012) A study of the blue-light-dependent phosphorylation, degradation, and photobody formation of Arabidopsis CRY2. Mol. Plant 5: 726-733.
  • Liu, H., Wang, Q., Liu, Y., Zhao, X., Imaizumi, T., Somers, D. E., Tobin, E. M., and Lin, C. (2013) The Arabidopsis photoreceptors CRY2 and ZTL mediate blue-light regulation of the transcription factor CIB1 by distinct mechanisms, Proc Natl Acad Sci U S A 110:17582-17587.
  • Meng Y, Li, H., Wang Q., Liu, B., and Lin C. (2013) Cryptochrome 2 (GmCRY2a) and CRY-interacting bHLH 1 (GmCIB1) mediates light regulation of transcription and leaf senescence in soybean (Glycine max), Plant Cell 25: 44054420.

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Inventors

  • Lin, Chentao

Other Information

Keywords

cryptochrome, CRY, cryptochrome dimerization, light-dependent dimerization, optogenetics, circadian clock, transcription regulation, protein translocation, DNA recombination, phosphoinositide metabolism, epigenetics change, reversible protein inactivation

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