| General information | | DisProt: | DP00078 | | Name: | Proto-oncogene protein c-fos | | Synonym(s): | FOS_HUMAN
Cellular oncogene fos
G0/G1 switch regulatory protein 7
Transcription factor c-Fos
| | First appeared in release: | Release 1.0 (08/01/2003) | | UniProt: | P01100 | | UniGene: | Hs.707896 | | SwissProt: | FOS_HUMAN | | TrEMBL: | | | NCBI (GI): | 120470 | | Source organism: | Homo sapiens (Human) | | Sequence length: | 380 | | Percent disordered: | 43% | | Homologues: | |
| Native sequence |
10 20 30 40 50 60
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MMFSGFNADY EASSSRCSSA SPAGDSLSYY HSPADSFSSM GSPVNAQDFC TDLAVSSANF - 60
IPTVTAISTS PDLQWLVQPA LVSSVAPSQT RAPHPFGVPA PSAGAYSRAG VVKTMTGGRA - 120
QSIGRRGKVE QLSPEEEEKR RIRRERNKMA AAKCRNRRRE LTDTLQAETD QLEDEKSALQ - 180
TEIANLLKEK EKLEFILAAH RPACKIPDDL GFPEEMSVAS LDLTGGLPEV ATPESEEAFT - 240
LPLLNDPEPK PSVEPVKSIS SMELKTEPFD DFLFPASSRP SGSETARSVP DMDLSGSFYA - 300
ADWEPLHSGS LGMGPMATEL EPLCTPVVTC TPSCTAYTSS FVFTYPEADS FPSCAAAHRK - 360
GSSSNEPSSD SLSSPTLLAL
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| Functional narrative |
Human c-Fos has a modular structure consisting of an N-terminal activation domain, a bZIP dimerization/DNA-binding domain, and a C-terminal domain that contains both acidic and proline-rich activation domains and is independent of the rest of the molecule. The C-terminal domain regulates various protein-protein interactions and interacts with TBP, TFIID, the acetyltransferase and coactivator CBP, and the regulatory transcription factor Smad3. The C-terminal domain of Fos has not been defined in structural terms, but the C-terminal activation domain of human c-Fos (residues 216-380)(Fos-AD) is essentially devoid of the stable helical or beta-sheet structure typical of globular proteins and c-Fos contains an intrinsically disordered yet biologically active activation domain. Fos-AD is a synthetic fragment that spans the human c-Fos C-terminal activation domain (residues 216-380). Fos-AD suppresses transcription of an AP-1 regulated gene and Fos-AD is functional for interactions with the target transcription factors of c-Fos.
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| Map of ordered and disordered regions |
Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.
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| Region 1 | | Type: | Disordered - Extended | | Name: | FosAD - Fragment | | Location: | 216 - 380 | | Length: | 165 | | Region sequence: |
MSVASLDLTGGLPEVATPESEEAFTLPLLNDPEPKPSVEPVKSISSMELKTEPFDDFLFP
ASSRPSGSETARSVPDMDLSGSFYAADWEPLHSGSLGMGPMATELEPLCTPVVTCTPSCT
AYTSSFVFTYPEADSFPSCAAAHRKGSSSNEPSSDSLSSPTLLAL | | Modification type: | Fragment
| | PDB: | | | Structural/functional type: | Function arises via a disorder to order transition
| | Functional classes: | Molecular assembly
| | Functional subclasses: | Autoregulatory
Protein-protein binding
| Detection methods:
- Circular dichroism (CD) spectroscopy, near-UV (DTT 1 mM; NaCl 1 M; sodium phosphate 10 mM)
- Nuclear magnetic resonance (NMR) (298 K; d10-DTT 1 mM; NaCl 150 mM; sodium phosphate 10 mM)
- Size exclusion/gel filtration chromatography (DTT 1 mM; NaCl 150 mM; sodium phosphate 10 mM)
| References:
- Campbell KM, Terrell AR, Laybourn PJ, Lumb KJ. "Intrinsic structural disorder of the C-terminal activation domain from the bZIP transcription factor Fos." Biochemistry. 2000; 39(10): 2708-13. PubMed: 10704222
- Flaugh SL, Lumb KJ. "Effects of macromolecular crowding on the intrinsically disordered proteins c-Fos and p27(Kip1)." Biomacromolecules. 2001; 2(2): 538-540. PubMed: 11749217
| Comments:
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| Comments |
It has been shown that the active acidic and proline-rich C-terminal activation domain of human c-Fos is structurally disordered and has the properties of an unfolded protein. It was found that disorder was not due to the deletion of a sequence necessary for structure. Structural disorder has also been found with the acidic activation domains from VP16, NF-kB, and p53. Results for c-Fos and for the p53 proline-rich activation domain have indicated that proline-rich activation domains can exhibit structural disorder. Proposed mechanistic advantages of these disordered protein domains include increased binding specificity at the expense of thermodynamic stability, regulation of proteolysis, and the ability to recognize a range of different proteins. The C-terminal activation domain contains a number of phosphorylation sites that moderate Fos activity. The conformational freedom of the structurally disordered C-terminal activation domain contributes to the functional diversity of c-Fos by allowing the formation of numerous protein complexes (with transcription factors and with regulatory kinases).
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