7vou

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The crystal structure of human forkhead box protein in complex with DNA 1

Structural highlights

7vou is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.1Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FOXL2_HUMAN Blepharophimosis-ptosis-epicanthus inversus syndrome plus;Blepharophimosis-ptosis-epicanthus inversus syndrome type 2;Maligant granulosa cell tumor of the ovary;NON RARE IN EUROPE: Primary ovarian failure;Blepharophimosis-ptosis-epicanthus inversus syndrome type 1. The disease is caused by variants affecting the gene represented in this entry. There is a mutational hotspot in the region coding for the poly-Ala domain, since 30% of all mutations in the ORF lead to poly-Ala expansions, resulting mainly in BPES type II. The disease is caused by variants affecting the gene represented in this entry.

Function

FOXL2_HUMAN Transcriptional regulator. Critical factor essential for ovary differentiation and maintenance, and repression of the genetic program for somatic testis determination. Prevents trans-differentiation of ovary to testis through transcriptional repression of the Sertoli cell-promoting gene SOX9 (By similarity). Has apoptotic activity in ovarian cells. Suppresses ESR1-mediated transcription of PTGS2/COX2 stimulated by tamoxifen (By similarity). Is a regulator of CYP19 expression (By similarity). Participates in SMAD3-dependent transcription of FST via the intronic SMAD-binding element (By similarity). Is a transcriptional repressor of STAR. Activates SIRT1 transcription under cellular stress conditions. Activates transcription of OSR2.[1] [2] [3] [4]

Publication Abstract from PubMed

Although both the p53 and forkhead box (FOX) family proteins are key transcription factors associated with cancer progression, their direct relationship is unknown. Here, we found that FOX family proteins bind to the non-canonical homotypic cluster of the p53 promoter region (TP53). Analysis of crystal structures of FOX proteins (FOXL2 and FOXA1) bound to the p53 homotypic cluster indicated that they interact with a 2:1 stoichiometry accommodated by FOX-induced DNA allostery. In particular, FOX proteins exhibited distinct dimerization patterns in recognition of the same p53-DNA; dimer formation of FOXA1 involved protein-protein interaction, but FOXL2 did not. Biochemical and biological functional analyses confirmed the cooperative binding of FOX proteins to the TP53 promoter for the transcriptional activation of TP53. In addition, up-regulation of TP53 was necessary for FOX proteins to exhibit anti-proliferative activity in cancer cells. These analyses reveal the presence of a discrete characteristic within FOX family proteins in which FOX proteins regulate the transcription activity of the p53 tumor suppressor via cooperative binding to the TP53 promoter in alternative dimer configurations.

FOXL2 and FOXA1 cooperatively assemble on the TP53 promoter in alternative dimer configurations.,Choi Y, Luo Y, Lee S, Jin H, Yoon HJ, Hahn Y, Bae J, Lee HH Nucleic Acids Res. 2022 Aug 26;50(15):8929-8946. doi: 10.1093/nar/gkac673. PMID:35920317[5]

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

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See Also

References

  1. ↑ Lee K, Pisarska MD, Ko JJ, Kang Y, Yoon S, Ryou SM, Cha KY, Bae J. Transcriptional factor FOXL2 interacts with DP103 and induces apoptosis. Biochem Biophys Res Commun. 2005 Oct 28;336(3):876-81. doi:, 10.1016/j.bbrc.2005.08.184. PMID:16153597 doi:http://dx.doi.org/10.1016/j.bbrc.2005.08.184
  2. ↑ Benayoun BA, Batista F, Auer J, Dipietromaria A, L'Hote D, De Baere E, Veitia RA. Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations. Hum Mol Genet. 2009 Feb 15;18(4):632-44. doi: 10.1093/hmg/ddn389. Epub 2008 Nov, 14. PMID:19010791 doi:http://dx.doi.org/10.1093/hmg/ddn389
  3. ↑ Laissue P, Lakhal B, Benayoun BA, Dipietromaria A, Braham R, Elghezal H, Philibert P, Saad A, Sultan C, Fellous M, Veitia RA. Functional evidence implicating FOXL2 in non-syndromic premature ovarian failure and in the regulation of the transcription factor OSR2. J Med Genet. 2009 Jul;46(7):455-7. doi: 10.1136/jmg.2008.065086. Epub 2009 May 7. PMID:19429596 doi:http://dx.doi.org/10.1136/jmg.2008.065086
  4. ↑ Kuo FT, Bentsi-Barnes IK, Barlow GM, Bae J, Pisarska MD. Sumoylation of forkhead L2 by Ubc9 is required for its activity as a transcriptional repressor of the Steroidogenic Acute Regulatory gene. Cell Signal. 2009 Dec;21(12):1935-44. doi: 10.1016/j.cellsig.2009.09.001. Epub, 2009 Sep 8. PMID:19744555 doi:10.1016/j.cellsig.2009.09.001
  5. ↑ Choi Y, Luo Y, Lee S, Jin H, Yoon HJ, Hahn Y, Bae J, Lee HH. FOXL2 and FOXA1 cooperatively assemble on the TP53 promoter in alternative dimer configurations. Nucleic Acids Res. 2022 Aug 26;50(15):8929-8946. doi: 10.1093/nar/gkac673. PMID:35920317 doi:http://dx.doi.org/10.1093/nar/gkac673

Contents


PDB ID 7vou

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