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. 1989 Aug;86(15):5698–5702. doi: 10.1073/pnas.86.15.5698

Association of charge clusters with functional domains of cellular transcription factors.

V Brendel 1, S Karlin 1
PMCID: PMC297697  PMID: 2569737

Abstract

Using rigorous statistical methods, we have identified and evaluated unusual properties of the distribution of charged residues within the sequences of eukaryotic cellular transcription factors. Virtually all transcription factors, including GAL4, c-Jun, C/EBP, CREB, Oct-1, Oct-2, Sp1, Egr-1, CTF-1, steroid and thyroid hormone receptors, and others, carry one or more highly significant charge clusters. For the most part these clusters (conserved within families of homologous proteins) are of positive net charge but contain also substantial numbers of acidic residues. Predominantly basic charge clusters are often, but not exclusively, associated with DNA-binding domains, and vice versa. Negative charge clusters of note occur only in the yeast protein PHO4 and in the proteins encoded at the Drosophila loci zeste (zeta) and knrl. This dearth of statistically significant negative charge clusters raises questions with respect to the generality of acidic activation domains. A number of sequences (Oct-1, Oct-2, zeste, Dhr23, E75, and knrl) contain multiple charge clusters together with one or more significantly long uncharged regions. The occurrence of multiple charge clusters is a rare phenomenon (found in less than 3% of all proteins, mainly in Drosophila developmental control proteins and in transactivators of eukaryotic DNA viruses). Most of the proteins with zinc-binding "fingers" carry a mixed charge cluster centered at the zinc-finger motif preceded by a long uncharged stretch, suggestive of a modular structure for these proteins.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blaisdell B. E., Karlin S. Distinctive charge configurations in proteins of the Epstein-Barr virus and possible functions. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6637–6641. doi: 10.1073/pnas.85.18.6637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bohmann D., Bos T. J., Admon A., Nishimura T., Vogt P. K., Tjian R. Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science. 1987 Dec 4;238(4832):1386–1392. doi: 10.1126/science.2825349. [DOI] [PubMed] [Google Scholar]
  3. Chang C. S., Kokontis J., Liao S. T. Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7211–7215. doi: 10.1073/pnas.85.19.7211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Christy B. A., Lau L. F., Nathans D. A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc finger" sequences. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7857–7861. doi: 10.1073/pnas.85.21.7857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cohen D. R., Curran T. fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen. Mol Cell Biol. 1988 May;8(5):2063–2069. doi: 10.1128/mcb.8.5.2063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Courey A. J., Tjian R. Analysis of Sp1 in vivo reveals multiple transcriptional domains, including a novel glutamine-rich activation motif. Cell. 1988 Dec 2;55(5):887–898. doi: 10.1016/0092-8674(88)90144-4. [DOI] [PubMed] [Google Scholar]
  7. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ford M. J., Anton I. A., Lane D. P. Nuclear protein with sequence homology to translation initiation factor eIF-4A. Nature. 1988 Apr 21;332(6166):736–738. doi: 10.1038/332736a0. [DOI] [PubMed] [Google Scholar]
  9. Ginsberg A. M., King B. O., Roeder R. G. Xenopus 5S gene transcription factor, TFIIIA: characterization of a cDNA clone and measurement of RNA levels throughout development. Cell. 1984 Dec;39(3 Pt 2):479–489. doi: 10.1016/0092-8674(84)90455-0. [DOI] [PubMed] [Google Scholar]
  10. Hartshorne T. A., Blumberg H., Young E. T. Sequence homology of the yeast regulatory protein ADR1 with Xenopus transcription factor TFIIIA. Nature. 1986 Mar 20;320(6059):283–287. doi: 10.1038/320283a0. [DOI] [PubMed] [Google Scholar]
  11. Hazel T. G., Nathans D., Lau L. F. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8444–8448. doi: 10.1073/pnas.85.22.8444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Herr W., Sturm R. A., Clerc R. G., Corcoran L. M., Baltimore D., Sharp P. A., Ingraham H. A., Rosenfeld M. G., Finney M., Ruvkun G. The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev. 1988 Dec;2(12A):1513–1516. doi: 10.1101/gad.2.12a.1513. [DOI] [PubMed] [Google Scholar]
  13. Hoeffler J. P., Meyer T. E., Yun Y., Jameson J. L., Habener J. F. Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA. Science. 1988 Dec 9;242(4884):1430–1433. doi: 10.1126/science.2974179. [DOI] [PubMed] [Google Scholar]
  14. Hollenberg S. M., Evans R. M. Multiple and cooperative trans-activation domains of the human glucocorticoid receptor. Cell. 1988 Dec 2;55(5):899–906. doi: 10.1016/0092-8674(88)90145-6. [DOI] [PubMed] [Google Scholar]
  15. Hope I. A., Mahadevan S., Struhl K. Structural and functional characterization of the short acidic transcriptional activation region of yeast GCN4 protein. Nature. 1988 Jun 16;333(6174):635–640. doi: 10.1038/333635a0. [DOI] [PubMed] [Google Scholar]
  16. Joseph L. J., Le Beau M. M., Jamieson G. A., Jr, Acharya S., Shows T. B., Rowley J. D., Sukhatme V. P. Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with "zinc-binding finger" structure. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7164–7168. doi: 10.1073/pnas.85.19.7164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kadonaga J. T., Carner K. R., Masiarz F. R., Tjian R. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell. 1987 Dec 24;51(6):1079–1090. doi: 10.1016/0092-8674(87)90594-0. [DOI] [PubMed] [Google Scholar]
  18. Karlin S., Blaisdell B. E., Mocarski E. S., Brendel V. A method to identify distinctive charge configurations in protein sequences, with application to human herpesvirus polypeptides. J Mol Biol. 1989 Jan 5;205(1):165–177. doi: 10.1016/0022-2836(89)90373-2. [DOI] [PubMed] [Google Scholar]
  19. Karlin S., Brendel V. Charge configurations in viral proteins. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9396–9400. doi: 10.1073/pnas.85.24.9396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Landschulz W. H., Johnson P. F., McKnight S. L. The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science. 1989 Mar 31;243(4899):1681–1688. doi: 10.1126/science.2494700. [DOI] [PubMed] [Google Scholar]
  21. Legrain M., De Wilde M., Hilger F. Isolation, physical characterization and expression analysis of the Saccharomyces cerevisiae positive regulatory gene PHO4. Nucleic Acids Res. 1986 Apr 11;14(7):3059–3073. doi: 10.1093/nar/14.7.3059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ma J., Ptashne M. A new class of yeast transcriptional activators. Cell. 1987 Oct 9;51(1):113–119. doi: 10.1016/0092-8674(87)90015-8. [DOI] [PubMed] [Google Scholar]
  23. Oro A. E., Ong E. S., Margolis J. S., Posakony J. W., McKeown M., Evans R. M. The Drosophila gene knirps-related is a member of the steroid-receptor gene superfamily. Nature. 1988 Dec 1;336(6198):493–496. doi: 10.1038/336493a0. [DOI] [PubMed] [Google Scholar]
  24. Paluh J. L., Orbach M. J., Legerton T. L., Yanofsky C. The cross-pathway control gene of Neurospora crassa, cpc-1, encodes a protein similar to GCN4 of yeast and the DNA-binding domain of the oncogene v-jun-encoded protein. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3728–3732. doi: 10.1073/pnas.85.11.3728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pirrotta V., Manet E., Hardon E., Bickel S. E., Benson M. Structure and sequence of the Drosophila zeste gene. EMBO J. 1987 Mar;6(3):791–799. doi: 10.1002/j.1460-2075.1987.tb04821.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ptashne M. Gene regulation by proteins acting nearby and at a distance. Nature. 1986 Aug 21;322(6081):697–701. doi: 10.1038/322697a0. [DOI] [PubMed] [Google Scholar]
  27. Santoro C., Mermod N., Andrews P. C., Tjian R. A family of human CCAAT-box-binding proteins active in transcription and DNA replication: cloning and expression of multiple cDNAs. Nature. 1988 Jul 21;334(6179):218–224. doi: 10.1038/334218a0. [DOI] [PubMed] [Google Scholar]
  28. Schleif R. DNA binding by proteins. Science. 1988 Sep 2;241(4870):1182–1187. doi: 10.1126/science.2842864. [DOI] [PubMed] [Google Scholar]
  29. Struhl K. Promoters, activator proteins, and the mechanism of transcriptional initiation in yeast. Cell. 1987 May 8;49(3):295–297. doi: 10.1016/0092-8674(87)90277-7. [DOI] [PubMed] [Google Scholar]
  30. Turner R., Tjian R. Leucine repeats and an adjacent DNA binding domain mediate the formation of functional cFos-cJun heterodimers. Science. 1989 Mar 31;243(4899):1689–1694. doi: 10.1126/science.2494701. [DOI] [PubMed] [Google Scholar]
  31. Vogt P. K., Bos T. J., Doolittle R. F. Homology between the DNA-binding domain of the GCN4 regulatory protein of yeast and the carboxyl-terminal region of a protein coded for by the oncogene jun. Proc Natl Acad Sci U S A. 1987 May;84(10):3316–3319. doi: 10.1073/pnas.84.10.3316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yates J. L., Warren N., Sugden B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. 1985 Feb 28-Mar 6Nature. 313(6005):812–815. doi: 10.1038/313812a0. [DOI] [PubMed] [Google Scholar]

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