The Rel family of eukaryotic transcription factors

Current Opinion in Structural Biology

Volumn 6, Issue 1, 1996, Pages 91-100

  Chytil, Milan ^a   Verdine, Gregory L ^a  

^a HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIMER; MONOMER; TRANSCRIPTION FACTOR;

CELL MATURATION; EUKARYOTIC CELL; INSECT; NONHUMAN; PRIORITY JOURNAL; PROTEIN DNA INTERACTION; PROTEIN FAMILY; PROTEIN STRUCTURE; REVIEW; VERTEBRATE;

EUKARYOTA; INSECTA; VERTEBRATA;

EID: 0029863521     PISSN: 0959440X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-440X(96)80100-X     Document Type: Article

References (75)

1. Baeuerle PA, Henkel T: Function and activation of NF-κB in the immune system. Annu Rev Immunol 1994, 12:141-179.
2. Miyamoto S, Verma IM: Rel/NF-κB/IκB story. Adv Cancer Res 1995, 46:255-292.
3. Siebenlist U, Franzoso G, Brown K: Structure, regulation and function of NF-κB. Annu Rev Cell Biol 1994, 10:405-455.
4. Ip YT, Reach M, Engstrom Y, Kadalayil L, Cai H, Gonzalez-Crespo S, Tatei K, Levine M: Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell 1993, 75:753-763.
5. Sen R, Baltimore D: Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986, 46:705-716.
6. Urban MB, Schreck R, Baeuerle PA: NF-κB contacts DNA by a heterodimer of the p50 and p65 subunit EMBO J 1991, 10:1817-1825.
7. Urban MB, Baeuerle PA: The role of the p50 and p65 subunits of NF-κB in the recognition of cognate sequences. N Biol 1991, 3:279-288.
8. Kunsch C, Ruben SM, Rosen CA: Selection of optimal κB/Rel DNA-binding motifs: interaction of both subunits of NF-κB with DNA is required for transcriptional activation. Mol Cell Biol 1992, 12:4412-4421.
9. Müller CW, Rey FA, Sodeoka M, Verdine GL, Harrison SC: Structure of the NF-κB p50 homodimer bound to DNA. Nature 1995, 373:311-317. Reports the crystal structure of the recombinant Rel homology region of p50-p50 bound to an 11 bp DNA element at 2.6 Å resolution. This study reveals that p50-p50 interacts symmetrically with the two half sites in DNA, which are separated by an odd number of base pairs (odd-numbered motif). The RHR is found to contain two constituent domains, one that makes sequence-specific contacts in the major groove of the recognition site and another that is responsible for dimerization and also makes several phosphate contacts. Both domains possess a fold that is related to that found in members of the immunoglobulin superfamily. Rel proteins are found to use a DNA-binding strategy unlike any other known protein, utilizing a long loop to make all but one of the sequence-specific contacts to the DNA. The structure provides insights into the characteristic differences among ReI proteins with regard to dimerization and DNA binding, and also provides insights into the locus of interactions with heterologous proteins such as IκB and HMG I(Y).
10. ••]. The RHR is found to contain two constituent domains, one that makes specific contacts in the major groove of the recognition site and another that is responsible for dimerization and also makes several phosphate contacts. Both domains possess a fold that is related to that found in members of the immunoglobulin super-family. Rel proteins are found to use a DNA-binding strategy unlike any other protein, utilizing a long loop to make all but one of the sequence-specific contacts to the DNA. The structure provides insights into the characteristic differences among Rel proteins with regard to dimerization and DNA binding, and also provides insights into the locus of interactions with heterologous proteins such as IκB and HMG I(Y).
11. ••]. Provides insights into the structural adjustments that accompany the switching of p50-p50 between its two DNA-binding motifs. Required follow-up reading to the original reports, which do not include comparative information.
12. Jones EY: The immunoglobulin superfamily. Curr Opin Struct Biol 1993, 3:846-852.
13. Ryu S-E, Kwong PD, Truneh A, Porter TG, Arthos J, Rosenberg M, Dai X, Xuong N, Axel R, Sweet RW, Hendrickson WA: Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature 1990, 348:419-426.
14. Wang J, Yan Y, Garrett TPJ, Liu J, Rodgers DW, Garlick RL, Tarr GE, Husain Y, Reinherz EL, Harrison SC: Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature 1990, 348:411-418.
15. Harris LJ, Larson SB, Hasel KW, Day J, Greenwood A, McPherson A: The three-dimensional structure of an intact monoclonal antibody for canine lymphoma. Nature 1992, 360:369-372.
16. Cho Y, Gorina S, Jeffery PD, Pavletich NP: Crystal structure of a p53 suppressor-DNA complex: understanding tumorigenic mutations. Science 1994, 265:346-355.
17. Liu J, Sodeoka M, Lane WS, Verdine GL: Evidence for an non-α-helical DNA-binding motif in the Rel homology region. Proc Natl Acad Sci USA 1994, 91:908-912.
18. Kumar S, Rabson AB, Gélinas C: The RxxRxRxxC motif conserved in all Rel/κB proteins is essential for the DNA-binding activity and redox regulation of the v-Rel oncoprotein. Mol Cell Biol 1992, 12:3094-3106.
19. Toledano MB, Ghosh D, Trinh F, Leonard WJ: N-terminal DNA-binding domains contribute to differential DNA-binding specificities of NF-κB p50 and p65. Mol Cell Biol 1993, 13:852-860.
20. Bressler P, Brown K, Timmer W, Bours V, Siebenlist U, Fauci AS: Mutational analysis of the p50 subunit of NF-κB and inhibition of NF-κB activity by trans-dominant p50 mutants. J Virol 1993, 67:288-293.
21. Beamer LJ, Pabo CO: Refined 1.8 Å crystal structure of the λ repressor-operator complex. J Mol Biol 1992, 227:177-196.
22. Liu J, Fan QR, Sodeoka M, Lane WS, Verdine GL: DNA binding by an amino acid residue in the C-terminal half of the Rel homology region. Chem Biol 1994, 1:47-55.
23. Pabo CO, Sauer RT: Transcription factors: structural families and principles of DNA recognition. Annu Rev Biochem 1992, 61:1053-1095.
24. Larson CJ, Verdine GL: The chemistry of protein-DNA interactions. In Bioorganic Chemistry: Nucleic Acids. Edited by Hecht S. New York: Oxford University Press; 1996:324-346.
25. Stanojevic D, Verdine GL: Deconstruction of GCN4/GCRE into a monomeric peptide-DNA complex. Nature Struct Biol 1995, 2:450-457. This study demonstrates that a 24 amino acid peptide containing the DNA 'reading head' of GCN4 binds DNA specifically when tethered to it through a disulfide bond. By comparing the binding strength of the tethered peptide to DNA containing a consensus versus a non-consensus site, it is shown that a sequence-specific Arg-G contact is significantly stronger than a non-specific Arg-phosphate contact.
26. LeClair KP, Blanar MA, Sharp PA: The p50 subunit of NF-κB associates with the NF-IL6 transcription factor. Proc Natl Acad Sci USA 1992, 89:8145-8149.
27. Stein B, Cogswell P, Baldwin AS Jr: Functional and physical associations between NF-κB and C/EBP family members: a Rel domain-bZip interaction. Mol Cell Biol 1993, 13:3964-3974.
28. Thanos D, Maniatis T: The high-mobility group protein HMG I-(Y) is required for NF-κB-dependent virus induction of the human IFN-β gene. Cell 1992, 71:777-789.
29. Ray A, Prefontaine KE: Physical association and functional antagonism between the p65 subunit of transcription factor NF-κB and the glucocorticoid receptor. Proc Natl Acad Sci USA 1994, 91:752-756.
30. Schreck R, Zorbas H, Winnacker EL, Baeuerle PA: The NF-κB transcription factor induces DNA bending which is modulated by its 65-kD subunit. Nucleic Acids Res 1990, 18:6497-6502.
31. Kuprash DV, Rice NR, Nedospasov SA: Homodimer of p50 (NF-κB1) does not introduce a substantial directed bend into DNA according to three different experimental assays. Nucleic Acids Res 1995, 23:427-433.
32. Falvo JV, Thanos D, Maniatis T: Reversal of intrinsic DNA bends in the IFN-β gene enhancer by transcription factors and the architectural protein HMG I(Y). Cell 1995, 83:1101-1111. This paper reveals that certain NF-κB sites contain an intrinsic bend, which is straightened upon binding to NF-κB. The binding of HMG I(Y) to the NF-KB-DNA complex is associated with subtle changes in the DNA conformation, but not the kind of radical bending that is brought about by other architectural DNA-binding proteins such as those containing an HMG box.
33. Falvo JV, Maniatis T: Virus induction of human IFN-β gene expression requires the assembly of an enhancesome. Cell 1995, 83:1091-1100. This paper demonstrates that an architecturally specific assembly of regulatory proteins on the enhancer, termed an 'enhancesome', is essential for activation of transcription. The enhancer serves as a template for the assembly of the enhancesome, and proteins that remodel DNA architecture are shown to play en essential role in producing a functional enhancesome.
34. Navia MA, Fitzgerald PMD, McKeever BM, Leu C-T, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP: Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 1989, 337:615-620.
35. Beg AA, Baldwin AS Jr: The IκB proteins: multifunctional regulators of Rel/NF-κB transcription factors. Genes Dev 1993, 7:2064-2070.
36. Gilmore TD, Morin PJ: The IκB proteins: members of a multifunctional family. Trends Genet 1993, 9:427-433.
37. Potter DA, Larson CJ, Eckes P, Schmid RM, Nabel GJ, Verdine GL, Sharp PA: Purification of the MHC class I transcription factor H2TF1: The full-length product of the lyt-10 proto-oncogene. J Biol Chem 1993, 268:18882-18890.
38. Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U: The oncoprotein Bcl-3 directly transactivates through KB motifs via association with DNA-binding p50B homodimers. Cell 1993, 72:729-739.
39. Wasserman SA: A conserved signal transduction pathway regulating the activity of the Rel-like proteins dorsal and NF-κB. Mol Cell Biol 1993, 4:767-771.
40. Henkel T, Machleidt T, Alkalay I, Krönke M, Ben-Neriah Y, Baeuerle PA: Rapid proteolysis of IκB-α is necessary for activation of transcription factor NF-κB. Nature 1993, 365:182-185.
41. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T: Signal-induced site-specific phosphorylation targets IκBα to the ubiquitin-proteasome pathway. Genes Dev 1995, 9:1586-1597.
42. Finco TS, Beg AA, Baldwin AS Jr: Inducible phosphorylation of IκBα is not sufficient for its dissociation from NF-κB and is inhibited by protease inhibitors. Proc Natl Acad Sci USA 1994, 91:11884-11888.
43. Miyamoto S, Maki MJ, Schmitt MJ, Hatanaka M, Verma IM: Tumor necrosis factor α-induced phosphorylation of IκBα is a signal for its degradation but not dissociation from NF-κB. Proc Natl Acad Sci USA 1994, 91:12740-12744.
44. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T: The ubiquitin-proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB. Cell 1994, 78:773-785.
45. Mellits KH, Hay RT, Goodbourn S: Proteolytic degradation of MAD3 (IκBα) and enhanced processing of the NF-κB precursor p105 are obligatory steps in the activation of NF-κB. Nucleic Acids Res 1993, 21:5059-5066.
46. Löwe J, Stock D, Jap B, Zwickl P, Baumeister W, Huber R: Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 Ȧ resolution. Science 1995, 268:533-539. This paper reveals the three-dimensional structure of a bacterial proteasome.
47. Kumar S, Gélinas C: IκBα-mediated inhibition of v-Rel DNA binding requires direct interaction with the RXXRXRXXC Rel/kappaB DNA-binding motif. Proc Natl Acad Sci USA 1993, 90:8962-8966.
48. Ganchi PA, Sun S-C, Greene WC, Ballard DW: IκB/MAD-3 masks the nuclear localization signal of NF-κB p65 and requires the trans-activation domain to inhibit NF-κB p65 binding. Mol Cell Biol 1992, 3:1339-1352.
49. Henkel T, Zabel U, Van Zee K, Müller JM, Fanning E, Baeuerle P: Intramolecular masking of the nuclear localization signal and dimerization domain in the precursor for the p50 NF-κB subunit. Cell 1992, 68:1121-1133.
50. Sodeoka M, Larson CJ, Chen L, Lane WS, Verdine GL: Limited proteolysis and site-directed mutagenesis of the NF-κB p50 DNA-binding subunit. BioMed Chem Lett 1993, 3:1095-1100.
51. Lehming N, McGuire S, Brickman JM, Ptashne M: Interactions of a Rel protein with its inhibitor. Proc Natl Acad Sci USA 1995, 92:10242-10246. This paper reports mutations in the Drosophila Rel homolog dorsal that disrupt the interaction with its IκB counterpart, cactus. These mutations lie in the canyon formed by the association of the dimerization domains.
52. Fraser JD, Strauss K, Weiss A: Signal transduction events leading to T-cell lymphokine gene expression. Immunol Today 1993, 14:357-362.
53. Crabtree GR, Clipstone NA: Signal transmission between the plasma membrane and the nucleus of T lymphocytes. Annu Rev Biochem 1994, 63:1045-1083.
54. Jain J, Loh C, Rao A: Transcriptional regulation of the IL-2 gene. Curr Opin Immunol 1995, 7:333-342.
55. Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR: Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science 1989, 246:1617-1620.
56. Mattila PS, Ullman KS, Fiering S, Emmel EA, McCutcheon M, Crabtree GR, Herzenber LA: The actions of cyclosporin A and FK506 suggest a novel step in the activation of T lymphocytes. EMBO J 1990, 9:4425-4433.
57. Flanagan WM, Corthésy B, Bram RJ, Crabtree GR: Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 1991, 352:803-807.
58. Rao A: NFATp: a transcription factor required for the coordinate induction of several cytokine genes. Immunol Today 1994, 15:274-281.
59. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 1991, 66:1-9.
60. Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA: X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell 1995, 82:507-522. This paper reveals the three-dimensional structure of the ternary complex formed between the immunosuppressant drug FK506, its small receptor FKBP12 and the Ser/Thr phosphatase calcineurin. The ternary complex is best described as a sandwich in which the drug is slathered between the two proteins, which are themselves in contact with one another. The FK506-FKBP12 complex binds a region of calcineurin adjacent to the phosphatase active site, thus allowing access to small molecules such as p-nitrophenyl phosphate, but sterically blocking access to large molecules such as phosphopeptides.
61. Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW et al.: Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature 1995, 378:641-644. This paper affords a comparison of the X-ray structure of free calcineurin with that of calcineurin complexed to the FKBP12-FK506 complex. It reveals the presence of an autoinhibitory structural element in calcineurin that binds the Zn/Fe active site in the free enzyme but is displaced upon formation of the ternary complex.
62. Schreiber SL, Crabtree GR: The mechanism of action of cyclosporin A and FK506. Immunol Today 1992, 13:136-142.
63. Jain J, McCaffrey PG, Miner Z, Kerppola TM, Lambert JN, Verdine GL, Curran T, Rao A: The T cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 1993, 365:352-353.
64. McCaffrey PG, Luo C, Kerppola TK, Jain J, Badalian TM, Ho AM, Burgeon E, Lane WS, Lambert JN, Curran T, Verdine GL, Rao A, Hogan PG: Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science 1993, 262:750-754.
65. Northrop JP, Ho SN, Chen L, Thomas DJ, Timmerman LA, Nolan GP, Admon A, Crabtree GR: NFAT components define a family of transcription factors targeted in T cell activation. Nature 1994, 369:497-502.
66. Ho SN, Thomas DJ, Timmerman LA, Li X, Francke U, Crabtree GR: NFATc3, a lymphoid specific NFATc family member that is calcium-regulated and exhibits distinct DNA binding activity. J Biol Chem 1995, 270:19898-19907.
67. Masuda ES, Naito Y, Tokumitsu H, Campbell D, Saito F, Hannum C, Arai K-I, Arai N: NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus. Mol Cell Biol 1995, 15:2697-2706.
68. Jain J, McCaffrey PG, Valge-Archer VE, Rao A: Nuclear factor of activated T cells contains Fos and Jun. Nature 1992, 356:801-804.
69. Northrop JP, Ullman KS, Crabtree GR: Characterization of the nuclear and cytoplasmic components of the lymphoid-specific nuclear factor of activated T cells (NF-AT) complex. J Biol Chem 1993, 268:2917-2923.
70. Jain J, Burgeon E, Badalian TM, Hogan PG, Rao A: A similar DNA-binding motif in NFAT family proteins and the Rel homology region. J Biol Chem 1995, 270:4138-4145.
71. 2 symmetry, NF-ATp is able to form a cooperative complex with only one of the two orientational isomers of Ap-1 ; thus NF-ATp locks the orientation of AP-1 on DNA. The mechanism of this orientational locking is shown to involve direct contacts between AP-1 and NF-ATp.
72. Glover JNM, Harrison SC: The crystal structure of the heterodimeric bZip transcription factor cFos:cJun bound to DNA. Nature 1994, 373:257-261.
73. Glover JNM, Chen L, Verdine GL, Harrison SC: A structural analysis of the bZip family of transcription factors: dimerization, DNA binding and interactions with other transcription factors. J Biomol Struct Dyn 1995, in press.
74. B promoter: enhancer-like sequences and their role in the regulation of class I gene expression. Cell 1986, 44:261-272.
75. 2-microglobulin genes. Proc Natl Acad Sci USA 1987, 84:2653-2657.