2wt7

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Crystal structure of the bZIP heterodimeric complex MafB:cFos bound to DNACrystal structure of the bZIP heterodimeric complex MafB:cFos bound to DNA

Structural highlights

2wt7 is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FOS_MOUSE] Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex, at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling (By similarity). Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum.[1] [2] [3] [4] [5] [MAFB_MOUSE] Acts as a transcriptional activator or repressor. Plays a pivotal role in regulating lineage-specific hematopoiesis by repressing ETS1-mediated transcription of erythroid-specific genes in myeloid cells. Required for monocytic, macrophage, podocyte and islet beta cell differentiation. Involved in renal tubule survival and F4/80 maturation. Activates the insulin and glucagon promoters. Together with PAX6, transactivates weakly the glucagon gene promoter through the G1 element. SUMO modification controls its transcriptional activity and ability to specify macrophage fate. Binds element G1 on the glucagon promoter. Involved either as an oncogene or as a tumor suppressor, depending on the cell context.[6] [7] [8] [9] [10] [11] [12]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The ability of basic leucine zipper transcription factors for homo- or heterodimerization provides a paradigm for combinatorial control of eukaryotic gene expression. It has been unclear, however, how facultative dimerization results in alternative DNA-binding repertoires on distinct regulatory elements. To unravel the molecular basis of such coupled preferences, we determined two high-resolution structures of the transcription factor MafB as a homodimer and as a heterodimer with c-Fos bound to variants of the Maf-recognition element. The structures revealed several unexpected and dimer-specific coiled-coil-heptad interactions. Based on these findings, we have engineered two MafB mutants with opposite dimerization preferences. One of them showed a strong preference for MafB/c-Fos heterodimerization and enabled selection of heterodimer-favoring over homodimer-specific Maf-recognition element variants. Our data provide a concept for transcription factor design to selectively activate dimer-specific pathways and binding repertoires.

Design of a bZip Transcription Factor with Homo/Heterodimer-Induced DNA-Binding Preference.,Pogenberg V, Consani Textor L, Vanhille L, Holton SJ, Sieweke MH, Wilmanns M Structure. 2014 Feb 11. pii: S0969-2126(14)00009-4. doi:, 10.1016/j.str.2013.12.017. PMID:24530283[13]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J. Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol. 2002 Aug;4(8):556-64. PMID:12134156 doi:http://dx.doi.org/10.1038/ncb822
  2. ↑ Monje P, Marinissen MJ, Gutkind JS. Phosphorylation of the carboxyl-terminal transactivation domain of c-Fos by extracellular signal-regulated kinase mediates the transcriptional activation of AP-1 and cellular transformation induced by platelet-derived growth factor. Mol Cell Biol. 2003 Oct;23(19):7030-43. PMID:12972619
  3. ↑ David JP, Mehic D, Bakiri L, Schilling AF, Mandic V, Priemel M, Idarraga MH, Reschke MO, Hoffmann O, Amling M, Wagner EF. Essential role of RSK2 in c-Fos-dependent osteosarcoma development. J Clin Invest. 2005 Mar;115(3):664-72. PMID:15719069 doi:http://dx.doi.org/10.1172/JCI22877
  4. ↑ Alfonso Pecchio AR, Cardozo Gizzi AM, Renner ML, Molina-Calavita M, Caputto BL. c-Fos activates and physically interacts with specific enzymes of the pathway of synthesis of polyphosphoinositides. Mol Biol Cell. 2011 Dec;22(24):4716-25. doi: 10.1091/mbc.E11-03-0259. Epub 2011, Oct 12. PMID:21998197 doi:http://dx.doi.org/10.1091/mbc.E11-03-0259
  5. ↑ Ferrero GO, Velazquez FN, Caputto BL. The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity. Oncogene. 2012 Jul 12;31(28):3381-91. doi: 10.1038/onc.2011.510. Epub 2011 Nov, 21. PMID:22105363 doi:http://dx.doi.org/10.1038/onc.2011.510
  6. ↑ Kelly LM, Englmeier U, Lafon I, Sieweke MH, Graf T. MafB is an inducer of monocytic differentiation. EMBO J. 2000 May 2;19(9):1987-97. PMID:10790365 doi:10.1093/emboj/19.9.1987
  7. ↑ Artner I, Le Lay J, Hang Y, Elghazi L, Schisler JC, Henderson E, Sosa-Pineda B, Stein R. MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells. Diabetes. 2006 Feb;55(2):297-304. PMID:16443760
  8. ↑ Moriguchi T, Hamada M, Morito N, Terunuma T, Hasegawa K, Zhang C, Yokomizo T, Esaki R, Kuroda E, Yoh K, Kudo T, Nagata M, Greaves DR, Engel JD, Yamamoto M, Takahashi S. MafB is essential for renal development and F4/80 expression in macrophages. Mol Cell Biol. 2006 Aug;26(15):5715-27. PMID:16847325 doi:26/15/5715
  9. ↑ Gosmain Y, Avril I, Mamin A, Philippe J. Pax-6 and c-Maf functionally interact with the alpha-cell-specific DNA element G1 in vivo to promote glucagon gene expression. J Biol Chem. 2007 Nov 30;282(48):35024-34. Epub 2007 Sep 27. PMID:17901057 doi:10.1074/jbc.M702795200
  10. ↑ Tillmanns S, Otto C, Jaffray E, Du Roure C, Bakri Y, Vanhille L, Sarrazin S, Hay RT, Sieweke MH. SUMO modification regulates MafB-driven macrophage differentiation by enabling Myb-dependent transcriptional repression. Mol Cell Biol. 2007 Aug;27(15):5554-64. Epub 2007 Jun 4. PMID:17548468 doi:10.1128/MCB.01811-06
  11. ↑ Nishimura W, Rowan S, Salameh T, Maas RL, Bonner-Weir S, Sell SM, Sharma A. Preferential reduction of beta cells derived from Pax6-MafB pathway in MafB deficient mice. Dev Biol. 2008 Feb 15;314(2):443-56. Epub 2007 Dec 23. PMID:18199433 doi:S0012-1606(07)01593-X
  12. ↑ Eychene A, Rocques N, Pouponnot C. A new MAFia in cancer. Nat Rev Cancer. 2008 Sep;8(9):683-93. PMID:19143053 doi:10.1038/nrc2460
  13. ↑ Pogenberg V, Consani Textor L, Vanhille L, Holton SJ, Sieweke MH, Wilmanns M. Design of a bZip Transcription Factor with Homo/Heterodimer-Induced DNA-Binding Preference. Structure. 2014 Feb 11. pii: S0969-2126(14)00009-4. doi:, 10.1016/j.str.2013.12.017. PMID:24530283 doi:http://dx.doi.org/10.1016/j.str.2013.12.017

2wt7, resolution 2.30Å

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