Chemically induced dimerization

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Scheme of chemically induced dimerization in which two macromolecules only interact in the presence of the inducer.

The chemically induced dimerization ( English Chemically Induced Dimerization , CID) is a biochemical process in which a dimerization of two macromolecules only in the presence of a small molecule , an enzyme is carried out or other Dimerisierungsinduktors.

properties

Chemically induced dimerizations consist of three components, the two macromolecules (mostly proteins ) to be bound to one another and the dimerization inducer. The bond to one another only takes place in the presence of the dimerization inducer. CID occur naturally z. B. on some nuclear receptors . In addition, various recombinant , selectively inducible dimerization systems have been developed through protein design. As a dimerization inductor, for. B. rapamycin (synonym sirolimus), FK506 (synonym tacrolimus) or a synthetic ligand such as AP20187 is used. The two dimerizing proteins are mostly used as fusion proteins with the proteins to be examined.

Applications

The CID enables protein-protein interactions to be initiated with low unspecific binding and time controllability. You will e.g. B. used to change the signal transduction in a cell, to change the localization, to activate proteins, and to generate inducible protein complexes . The use of CID as a logical gate in biocomputing is being investigated.

Chemically Induced Dimerization Systems

Target proteins Dimerization inductor source
FKBP FKBP FK1012
FKBP Calcineurin A (CNA) FK506
FKBP CyP- Fas FKCsA
FKBP FRB domain of the mTOR Rapamycin
GyrB GyrB Coumermycin
GAI GID1 Gibberellin
ABI PYL Abscisic acid
Snap tag HaloTag HaXS
14-3-3 PMA2 Fusicoccin

history

The first artificial CID system was developed in 1993 by Fegan et al. developed. A derivative of FK506 , FK1012 , was used as a dimerization inductor .

literature

Individual evidence

  1. ↑ a b c A. Fegan, B. White, JC Carlson, CR Wagner: Chemically controlled protein assembly: techniques and applications. In: Chemical Reviews . Volume 110, Number 6, June 2010, pp. 3315-3336, ISSN  1520-6890 . doi: 10.1021 / cr8002888 . PMID 20353181 .
  2. ↑ N. Kacherovsky, MA Harkey, CA Blau, CM Giachelli, SH Pun: Combination of Sleeping Beauty transposition and chemically induced dimerization selection for robust production of engineered cells. In: Nucleic acids research. Volume 40, number 11, June 2012, p. E85, ISSN  1362-4962 . doi: 10.1093 / nar / gks213 . PMID 22402491 . PMC 3367214 (free full text).
  3. ↑ a b M. Skwarczynska, M. Molzan, C. Ottmann: Activation of NF-kappaB signaling by fusicoccin-induced dimerization. In: Proceedings of the National Academy of Sciences . Volume 110, Number 5, January 2013, pp. E377-E386, ISSN  1091-6490 . doi: 10.1073 / pnas.1212990110 . PMID 23269842 . PMC 3562809 (free full text).
  4. ↑ SJ Kopytek, RF Standaert, JC Dyer, JC Hu: Chemically induced dimerization of dihydrofolate reductase by a homobifunctional dimer of methotrexate. In: Chemistry & biology. Volume 7, Number 5, May 2000, pp. 313-321, ISSN  1074-5521 . PMID 10801470 .
  5. ^ BR White, Q. Li, CR Wagner: Chemically induced self-assembly of enzyme nanorings. In: Methods in molecular biology (Clifton, NJ). Volume 743, 2011, pp. 17-26, ISSN  1940-6029 . doi : 10.1007 / 978-1-61779-132-1_2 . PMID 21553179 .
  6. ↑ T. Miyamoto, R. DeRose, A. Suarez, T. Ueno, M. Chen, TP Sun, MJ Wolfgang, C. Mukherjee, DJ Meyers, T. Inoue: Rapid and orthogonal logic gating with a gibberellin-induced dimerization system . In: Nature chemical biology. Volume 8, Number 5, May 2012, pp. 465-470, ISSN  1552-4469 . doi: 10.1038 / nchembio.922 . PMID 22446836 . PMC 3368803 (free full text).
  7. ↑ DM Spencer, TJ Wandless, SL Schreiber, GR Crabtree: Controlling signal transduction with synthetic ligands. In: Science. Volume 262, Number 5136, November 1993, ISSN  0036-8075 , pp. 1019-1024, doi: 10.1126 / science.7694365 , PMID 7694365 .
  8. ↑ SN Ho, SR Biggar, DM Spencer, SL Schreiber, GR Crabtree: Dimeric ligands define a role for transcriptional activation domains in reinitiation. In: Nature. Volume 382, ​​Number 6594, August 1996, ISSN  0028-0836 , pp. 822-826, doi: 10.1038 / 382822a0 . PMID 8752278 .
  9. ↑ PJ Belshaw, SN Ho, GR Crabtree, SL Schreiber: Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins. In: Proceedings of the National Academy of Sciences . Volume 93, number 10, May 1996, ISSN  0027-8424 , pp. 4604-4607, doi: 10.1073 / pnas.93.10.4604 , PMID 8643450 , PMC 39324 (free full text).
  10. ^ VM Rivera, T. Clackson, S. Natesan, R. Pollock, JF Amara, T. Keenan, SR Magari, T. Phillips, NL Courage, F. Cerasoli, DA Holt, M. Gilman: A humanized system for pharmacologic control of gene expression. In: Nature medicine. Volume 2, Number 9, September 1996, ISSN  1078-8956 , pp. 1028-1032, doi: 10.1038 / nm0996-1028 , PMID 8782462 .
  11. ↑ MA Farrar, J. Alberol-Ila, RM Perlmutter: Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. In: Nature. Volume 383, Number 6596, September 1996, ISSN  0028-0836 , pp. 178-181, doi: 10.1038 / 383178a0 . PMID 8774884 .
  12. ↑ T. Miyamoto, R. DeRose, A. Suarez, T. Ueno, M. Chen, TP Sun, MJ Wolfgang, C. Mukherjee, DJ Meyers, T. Inoue: Rapid and orthogonal logic gating with a gibberellin-induced dimerization system . In: Nature chemical biology. Volume 8, Number 5, May 2012, ISSN  1552-4469 , pp. 465-470, doi: 10.1038 / nchembio.922 . PMID 22446836 , PMC 3368803 (free full text).
  13. ↑ F.-S. Liang, WQ Ho, GR Crabtree: Engineering the ABA Plant Stress Pathway for Regulation of Induced Proximity . In: Science Signaling . tape 4 , no. 164 , March 15, 2011, ISSN  1937-9145 , p. rs2 – rs2 , doi : 10.1126 / scisignal.2001449 , PMID 21406691 , PMC 3110149 (free full text) - ( sciencemag.org [accessed October 11, 2019]).
  14. ↑ D. Erhart, M. Zimmermann, O. Jacques, MB Wittwer, B. Ernst, E. Constable, M. Zvelebil, F. Beaufils, MP Wymann: Chemical development of intracellular protein heterodimerizers. In: Chemistry & biology. Volume 20, number 4, April 2013, ISSN  1879-1301 , pp. 549-557, doi: 10.1016 / j.chembiol.2013.03.010 . PMID 23601644 .