Chemically induced dimerization

Chemically Induced Dimerization (CID) is a biological mechanism in which two proteins bind only in the presence of a certain small molecule, enzyme or other dimerizing agent.[1] Genetically engineered CID systems are used in biological research to control protein localization, to manipulate signalling pathways and to induce protein activation.[2]

Schematic of chemically induced dimerization. Two proteins that do not normally interact (top) bind in the presence of a dimerizing agent (bottom).

History

The first small molecule CID system was developed in 1993 and used FK1012, a derivative of the drug tacrolimus (FK506), to induce homo-dimerization of FKBP.[3] This system was used in vivo to induce binding between cell surface receptors which could not bind in the normal way because they lacked the transmembrane and extracellular domain. Addition of FK1012 to the cells caused signal transduction.

Chemically induced dimerization systems
Target proteins Dimerizing agent References
FKBP FKBP FK1012 [4]
FKBP Calcineurin A (CNA) FK506 [5]
FKBP CyP-Fas FKCsA [6]
FKBP FRB (FKBP-rapamycin-binding) domain of mTOR Rapamycin [7]
GyrB GyrB Coumermycin [8]
GAI GID1 (gibberellin insensitive dwarf 1) Gibberellin [9]
SNAP-tag HaloTag HaXS [10]
eDHFR HaloTag TMP-HTag [11]
Bcl-xL Fab (AZ1) ABT-737 [12]

Applications

CID has been used for a number of applications in biomedical research. In most applications each dimerizing protein is expressed as part of a fusion construct with other proteins of interest. Adding the chemical dimerizing agent brings both constructs into proximity with each other and induces interactions between the proteins of interest. CID has been used to regulate and monitor gene transcription, signal transduction and post translational modifications in proteins.

Recently, CID has also been used to create a basic component of biocomputers, logic gates, from genetically manipulated cells.[13] In this application, two independent CID systems, one based on plant proteins and one based on bacterial proteins are expressed in the same cell. Each set of proteins can be induced to dimerize by the addition of a separate chemical. By creating fusion proteins with the dimerizing proteins, membrane bound proteins and proteins that activate cell ruffling an AND gate and OR gate can be created that take chemical dimerizing agents as inputs and returns a ruffled or unruffled state as output.

References
  1. Kopytek, SJ; Standaert, RF; Dyer, JC; Hu, JC (May 2000). "Chemically induced dimerization of dihydrofolate reductase by a homobifunctional dimer of methotrexate". Chemistry & Biology. 7 (5): 313–21. doi:10.1016/s1074-5521(00)00109-5. PMID 10801470.
  2. Fegan, A; White, B; Carlson, JC; Wagner, CR (Jun 9, 2010). "Chemically controlled protein assembly: techniques and applications". Chemical Reviews. 110 (6): 3315–36. doi:10.1021/cr8002888. PMID 20353181.
  3. Fegan, A; White, B; Carlson, JC; Wagner, CR (Jun 9, 2010). "Chemically controlled protein assembly: techniques and applications". Chemical Reviews. 110 (6): 3315–36. doi:10.1021/cr8002888. PMID 20353181.
  4. Spencer, DM; Wandless, TJ; Schreiber, SL; Crabtree, GR (Nov 12, 1993). "Controlling signal transduction with synthetic ligands". Science. 262 (5136): 1019–24. doi:10.1126/science.7694365. PMID 7694365.
  5. Ho, SN; Biggar, SR; Spencer, DM; Schreiber, SL; Crabtree, GR (Aug 29, 1996). "Dimeric ligands define a role for transcriptional activation domains in reinitiation". Nature. 382 (6594): 822–6. doi:10.1038/382822a0. PMID 8752278.
  6. Belshaw, PJ; Ho, SN; Crabtree, GR; Schreiber, SL (May 14, 1996). "Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins". Proceedings of the National Academy of Sciences of the United States of America. 93 (10): 4604–7. doi:10.1073/pnas.93.10.4604. PMC 39324. PMID 8643450.
  7. Rivera, VM; Clackson, T; Natesan, S; Pollock, R; Amara, JF; Keenan, T; Magari, SR; Phillips, T; Courage, NL; Cerasoli F, Jr; Holt, DA; Gilman, M (September 1996). "A humanized system for pharmacologic control of gene expression". Nature Medicine. 2 (9): 1028–32. doi:10.1038/nm0996-1028. PMID 8782462.
  8. Farrar, MA; Alberol-Ila, J; Perlmutter, RM (Sep 12, 1996). "Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization". Nature. 383 (6596): 178–81. doi:10.1038/383178a0. PMID 8774884.
  9. Miyamoto, T; DeRose, R; Suarez, A; Wittwer, M; Ernst, B; Constable, E; Wolfgang, MJ; Mukherjee, C; Meyers, DJ; Inoue, T (Mar 25, 2012). "Rapid and orthogonal logic gating with a gibberellin-induced dimerization system". Nature Chemical Biology. 8 (5): 465–70. doi:10.1038/nchembio.922. PMC 3368803. PMID 22446836.
  10. Erhart, D; Zimermann, M; Jacques, O; Jacques, O; Wittwer, M; Ernst, B; Constable, E; Zvelebil, M; Beaufils, F; Wymann, M (Apr 18, 2013). "Chemical development of intracellular protein heterodimerizers". Chemistry and Biology. 20 (4): 549–57. doi:10.1016/j.chembiol.2013.03.010. PMID 23601644.
  11. Ballister, E; Aonbangkhen, C; Mayo, A; Lampson, M; Chenoweth, D (Nov 17, 2014). "Localized light-induced protein dimerization in living cells using a photocaged dimerizer". Nature Communications. 5 (5475). doi:10.1038/ncomms6475. PMC 4308733. PMID 25400104.
  12. Hill, Z; Martinko, A; Nguyen, D; Wells, J (Dec 4, 2017). "Human antibody-based chemically induced dimerizers for cell therapeutic applications". Nature Chemical Biology. 14 (2): 112–117. doi:10.1038/NCHEMBIO.2529. PMC 6352901. PMID 29200207.
  13. Miyamoto, T; DeRose, R; Suarez, A; Ueno, T; Chen, M; Sun, TP; Wolfgang, MJ; Mukherjee, C; Meyers, DJ; Inoue, T (Mar 25, 2012). "Rapid and orthogonal logic gating with a gibberellin-induced dimerization system". Nature Chemical Biology. 8 (5): 465–70. doi:10.1038/nchembio.922. PMC 3368803. PMID 22446836.
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