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MeSH Review


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Disease relevance of Dimerization

  • Analysis of cDNA mutants expressed in E. coli and Drosophila cells reveals that the N-terminal portion of CTF-1 is sufficient for site-specific DNA recognition, protein dimerization, and adenovirus replication [1].
  • The 2.6 A resolution crystal structure of Thermotoga maritima CheA (290-671) histidine kinase reveals a dimer where the functions of dimerization, ATP binding, and regulation are segregated into domains [2].
  • Human T-cell leukaemia virus type I (HTLV-I) Tax protein increases the DNA binding of many cellular transcription factors that contain a basic region-leucine zipper (bZIP) DNA-binding domain. bZIP domains comprise a leucine-rich dimerization motif and a basic region that mediates DNA contact [3].
  • The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants of FRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization [4].
  • E2F1 was the only family member more abundant in the melanoma cells compared with normal melanocytes, and the approximately fivefold increase in DNA binding activity could be accounted for mostly by a similar increase in the levels of the dimerization partner DP1 [5].

Psychiatry related information on Dimerization


High impact information on Dimerization

  • Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation [7].
  • Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors [8].
  • Briefly, binding of GH to GH receptor induces receptor dimerization and activation of the tyrosine kinase JAK2 [9].
  • PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking [10].
  • Dimeric p50(cdc37) binds to surfaces of the Hsp90 N-domain implicated in ATP-dependent N-terminal dimerization and association with the middle segment of the chaperone [11].

Chemical compound and disease context of Dimerization

  • Here we show that a glycine-to-cysteine substitution at position 375 (Gly375Cys) in human FGFR3 causes ligand-independent dimerization and phosphorylation of FGFR3 and that the equivalent substitution at position 369 (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimicking human achondroplasia [12].
  • These experimental results support a model in which HIV-1 RNA dimerizes by forming an interstrand quadruple helix stabilized by guanine (and/or purine)-base tetrads in analogy to the well-known dimerization of telomeric DNA [13].
  • This result indicated that MEN 2A mutations induced ligand-independent dimerization of the c-Ret protein on the cell surface, leading to activation of its intrinsic tyrosine kinase [14].
  • A synthetic 19-mer peptide covering part of this tryptophan repeat motif was recently shown to inhibit human immunodeficiency viruses type 1 reverse transcriptase subunit dimerization (Divita, G., Restle, T., Goody, R. S., Chermann, J.-C., and Baillon, J. G. (1994) J. Biol. Chem. 269, 13080-13083) [15].
  • Peroxynitrite induces covalent dimerization of epidermal growth factor receptors in A431 epidermoid carcinoma cells [16].

Biological context of Dimerization


Anatomical context of Dimerization

  • Receptor dimerization is ubiquitous to the action of all receptor tyrosine kinases, and in the case of dimeric ligands, such as the stem cell factor (SCF), it was attributed to ligand bivalency [21].
  • On a cell membrane containing both proteins, HFE would 'lie down' parallel to the membrane, such that the HFE helices that delineate the counterpart of the MHC peptide-binding groove make extensive contacts with helices in the TfR dimerization domain [22].
  • Our findings indicate that Mix.1 participates in a BMP-4 signalling pathway to pattern ventral mesoderm, and suggest a model whereby dimerization of homeodomain proteins regulates dorsal-ventral patterning [23].
  • An enzyme, identified as a nerve transglutaminase, was purified from regenerating optic nerves of fish and was found to catalyze dimerization of human IL-2 [24].
  • Coumermycin- induced L-selectin dimerization resulted in an approximately fourfold increase in binding of phosphomanan monoester core complex (PPME), a natural mimic of an L-selectin ligand, comparable to that observed after leukocyte activation [25].

Associations of Dimerization with chemical compounds


Gene context of Dimerization

  • Moreover, EGFR ligands functionally inactivate the EGFR-CD45 chimera in a manner that is dependent on dimerization of the chimeric protein [30].
  • The region of GAL11 affected by the P mutation is evidently functionally inert in ordinary cells, suggesting that this mutation is of no functional significance beyond creating an artificial target for the GAL4 dimerization fragment [31].
  • The P mutation confers upon GAL11, a component of the RNA polymerase II holoenzyme, the ability to interact with a portion of the dimerization region of GAL4 [31].
  • However, the dimerization domains of TRF1 and TRF2 did not interact, suggesting that these proteins exist predominantly as homodimers [32].
  • The susceptibility of a cell to a death signal is determined by these competing dimerizations in which levels of Bad influence the effectiveness of Bcl-2 versus Bcl-xL in repressing death [33].

Analytical, diagnostic and therapeutic context of Dimerization


  1. The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain. Mermod, N., O'Neill, E.A., Kelly, T.J., Tjian, R. Cell (1989) [Pubmed]
  2. Structure of CheA, a signal-transducing histidine kinase. Bilwes, A.M., Alex, L.A., Crane, B.R., Simon, M.I. Cell (1999) [Pubmed]
  3. Recognition of bZIP proteins by the human T-cell leukaemia virus transactivator Tax. Perini, G., Wagner, S., Green, M.R. Nature (1995) [Pubmed]
  4. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Choi, J., Chen, J., Schreiber, S.L., Clardy, J. Science (1996) [Pubmed]
  5. Deregulated E2F transcriptional activity in autonomously growing melanoma cells. Halaban, R., Cheng, E., Smicun, Y., Germino, J. J. Exp. Med. (2000) [Pubmed]
  6. The 'delta pH'-probe 9-aminoacridine: response time, binding behaviour and dimerization at the membrane. Grzesiek, S., Dencher, N.A. Biochim. Biophys. Acta (1988) [Pubmed]
  7. Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. Mellado, M., Rodríguez-Frade, J.M., Mañes, S., Martínez-A, C. Annu. Rev. Immunol. (2001) [Pubmed]
  8. Gp130 and the interleukin-6 family of cytokines. Taga, T., Kishimoto, T. Annu. Rev. Immunol. (1997) [Pubmed]
  9. Mechanism of signaling by growth hormone receptor. Argetsinger, L.S., Carter-Su, C. Physiol. Rev. (1996) [Pubmed]
  10. PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking. Taylor, S.S., Haste, N.M., Ghosh, G. Cell (2005) [Pubmed]
  11. The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Roe, S.M., Ali, M.M., Meyer, P., Vaughan, C.K., Panaretou, B., Piper, P.W., Prodromou, C., Pearl, L.H. Cell (2004) [Pubmed]
  12. Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. Chen, L., Adar, R., Yang, X., Monsonego, E.O., Li, C., Hauschka, P.V., Yayon, A., Deng, C.X. J. Clin. Invest. (1999) [Pubmed]
  13. Evidence for interstrand quadruplex formation in the dimerization of human immunodeficiency virus 1 genomic RNA. Sundquist, W.I., Heaphy, S. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  14. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Asai, N., Iwashita, T., Matsuyama, M., Takahashi, M. Mol. Cell. Biol. (1995) [Pubmed]
  15. Interface peptides as structure-based human immunodeficiency virus reverse transcriptase inhibitors. Divita, G., Baillon, J.G., Rittinger, K., Chermann, J.C., Goody, R.S. J. Biol. Chem. (1995) [Pubmed]
  16. Peroxynitrite induces covalent dimerization of epidermal growth factor receptors in A431 epidermoid carcinoma cells. van der Vliet, A., Hristova, M., Cross, C.E., Eiserich, J.P., Goldkorn, T. J. Biol. Chem. (1998) [Pubmed]
  17. Molecular basis of sulfite oxidase deficiency from the structure of sulfite oxidase. Kisker, C., Schindelin, H., Pacheco, A., Wehbi, W.A., Garrett, R.M., Rajagopalan, K.V., Enemark, J.H., Rees, D.C. Cell (1997) [Pubmed]
  18. Characterization and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor. Fawell, S.E., Lees, J.A., White, R., Parker, M.G. Cell (1990) [Pubmed]
  19. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Ogiso, H., Ishitani, R., Nureki, O., Fukai, S., Yamanaka, M., Kim, J.H., Saito, K., Sakamoto, A., Inoue, M., Shirouzu, M., Yokoyama, S. Cell (2002) [Pubmed]
  20. An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers. Sun, X.H., Baltimore, D. Cell (1991) [Pubmed]
  21. The fourth immunoglobulin domain of the stem cell factor receptor couples ligand binding to signal transduction. Blechman, J.M., Lev, S., Barg, J., Eisenstein, M., Vaks, B., Vogel, Z., Givol, D., Yarden, Y. Cell (1995) [Pubmed]
  22. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Bennett, M.J., Lebrón, J.A., Bjorkman, P.J. Nature (2000) [Pubmed]
  23. BMP-4-responsive regulation of dorsal-ventral patterning by the homeobox protein Mix.1. Mead, P.E., Brivanlou, I.H., Kelley, C.M., Zon, L.I. Nature (1996) [Pubmed]
  24. A transglutaminase that converts interleukin-2 into a factor cytotoxic to oligodendrocytes. Eitan, S., Schwartz, M. Science (1993) [Pubmed]
  25. Regulation of L-selectin-mediated rolling through receptor dimerization. Li, X., Steeber, D.A., Tang, M.L., Farrar, M.A., Perlmutter, R.M., Tedder, T.F. J. Exp. Med. (1998) [Pubmed]
  26. Structural basis for FGF receptor dimerization and activation. Plotnikov, A.N., Schlessinger, J., Hubbard, S.R., Mohammadi, M. Cell (1999) [Pubmed]
  27. A novel peptide recognition mode revealed by the X-ray structure of a core U2AF35/U2AF65 heterodimer. Kielkopf, C.L., Rodionova, N.A., Green, M.R., Burley, S.K. Cell (2001) [Pubmed]
  28. Multiple cell type-specific proteins differentially regulate target sequence recognition by the alpha retinoic acid receptor. Glass, C.K., Devary, O.V., Rosenfeld, M.G. Cell (1990) [Pubmed]
  29. Crystal structure of the VHS and FYVE tandem domains of Hrs, a protein involved in membrane trafficking and signal transduction. Mao, Y., Nickitenko, A., Duan, X., Lloyd, T.E., Wu, M.N., Bellen, H., Quiocho, F.A. Cell (2000) [Pubmed]
  30. Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase. Desai, D.M., Sap, J., Schlessinger, J., Weiss, A. Cell (1993) [Pubmed]
  31. Contact with a component of the polymerase II holoenzyme suffices for gene activation. Barberis, A., Pearlberg, J., Simkovich, N., Farrell, S., Reinagel, P., Bamdad, C., Sigal, G., Ptashne, M. Cell (1995) [Pubmed]
  32. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Broccoli, D., Smogorzewska, A., Chong, L., de Lange, T. Nat. Genet. (1997) [Pubmed]
  33. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Yang, E., Zha, J., Jockel, J., Boise, L.H., Thompson, C.B., Korsmeyer, S.J. Cell (1995) [Pubmed]
  34. Structural basis for inhibition of receptor protein-tyrosine phosphatase-alpha by dimerization. Bilwes, A.M., den Hertog, J., Hunter, T., Noel, J.P. Nature (1996) [Pubmed]
  35. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Boccaccio, C., Andò, M., Tamagnone, L., Bardelli, A., Michieli, P., Battistini, C., Comoglio, P.M. Nature (1998) [Pubmed]
  36. Dimerization of human growth hormone by zinc. Cunningham, B.C., Mulkerrin, M.G., Wells, J.A. Science (1991) [Pubmed]
  37. The cytomegalovirus DNA polymerase subunit UL44 forms a C clamp-shaped dimer. Appleton, B.A., Loregian, A., Filman, D.J., Coen, D.M., Hogle, J.M. Mol. Cell (2004) [Pubmed]
  38. The vascular smooth muscle alpha-actin gene is reactivated during cardiac hypertrophy provoked by load. Black, F.M., Packer, S.E., Parker, T.G., Michael, L.H., Roberts, R., Schwartz, R.J., Schneider, M.D. J. Clin. Invest. (1991) [Pubmed]
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