4yo2

Structure of E2F8, an atypical member of E2F family of transcription factorsStructure of E2F8, an atypical member of E2F family of transcription factors

Structural highlights

4yo2 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 3.073Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

E2F8_HUMAN Atypical E2F transcription factor that participates in various processes such as angiogenesis and polyploidization of specialized cells. Mainly acts as a transcription repressor that binds DNA independently of DP proteins and specifically recognizes the E2 recognition site 5'-TTTC[CG]CGC-3'. Directly represses transcription of classical E2F transcription factors such as E2F1: component of a feedback loop in S phase by repressing the expression of E2F1, thereby preventing p53/TP53-dependent apoptosis. Plays a key role in polyploidization of cells in placenta and liver by regulating the endocycle, probably by repressing genes promoting cytokinesis and antagonizing action of classical E2F proteins (E2F1, E2F2 and/or E2F3). Required for placental development by promoting polyploidization of trophoblast giant cells. Acts as a promoter of sprouting angiogenesis, possibly by acting as a transcription activator: associates with HIF1A, recognizes and binds the VEGFA promoter, which is different from canonical E2 recognition site, and activates expression of the VEGFA gene.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

The mammalian cell cycle is controlled by the E2F family of transcription factors. Typical E2Fs bind to DNA as heterodimers with the related dimerization partner (DP) proteins, whereas the atypical E2Fs, E2F7 and E2F8 contain two DNA-binding domains (DBDs) and act as repressors. To understand the mechanism of repression, we have resolved the structure of E2F8 in complex with DNA at atomic resolution. We find that the first and second DBDs of E2F8 resemble the DBDs of typical E2F and DP proteins, respectively. Using molecular dynamics simulations, biochemical affinity measurements and chromatin immunoprecipitation, we further show that both atypical and typical E2Fs bind to similar DNA sequences in vitro and in vivo. Our results represent the first crystal structure of an E2F protein with two DBDs, and reveal the mechanism by which atypical E2Fs can repress canonical E2F target genes and exert their negative influence on cell cycle progression.

Structural insights into the DNA-binding specificity of E2F family transcription factors.,Morgunova E, Yin Y, Jolma A, Dave K, Schmierer B, Popov A, Eremina N, Nilsson L, Taipale J Nat Commun. 2015 Dec 3;6:10050. doi: 10.1038/ncomms10050. PMID:26632596^[5]

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

References

↑ Logan N, Graham A, Zhao X, Fisher R, Maiti B, Leone G, La Thangue NB. E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7. Oncogene. 2005 Jul 21;24(31):5000-4. PMID:15897886 doi:http://dx.doi.org/10.1038/sj.onc.1208703
↑ Christensen J, Cloos P, Toftegaard U, Klinkenberg D, Bracken AP, Trinh E, Heeran M, Di Stefano L, Helin K. Characterization of E2F8, a novel E2F-like cell-cycle regulated repressor of E2F-activated transcription. Nucleic Acids Res. 2005 Sep 22;33(17):5458-70. Print 2005. PMID:16179649 doi:http://dx.doi.org/10.1093/nar/gki855
↑ Zalmas LP, Zhao X, Graham AL, Fisher R, Reilly C, Coutts AS, La Thangue NB. DNA-damage response control of E2F7 and E2F8. EMBO Rep. 2008 Mar;9(3):252-9. doi: 10.1038/sj.embor.7401158. Epub 2008 Jan 18. PMID:18202719 doi:http://dx.doi.org/10.1038/sj.embor.7401158
↑ Weijts BG, Bakker WJ, Cornelissen PW, Liang KH, Schaftenaar FH, Westendorp B, de Wolf CA, Paciejewska M, Scheele CL, Kent L, Leone G, Schulte-Merker S, de Bruin A. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J. 2012 Oct 3;31(19):3871-84. doi: 10.1038/emboj.2012.231. Epub 2012 Aug 17. PMID:22903062 doi:http://dx.doi.org/10.1038/emboj.2012.231
↑ Morgunova E, Yin Y, Jolma A, Dave K, Schmierer B, Popov A, Eremina N, Nilsson L, Taipale J. Structural insights into the DNA-binding specificity of E2F family transcription factors. Nat Commun. 2015 Dec 3;6:10050. doi: 10.1038/ncomms10050. PMID:26632596 doi:http://dx.doi.org/10.1038/ncomms10050

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OCA

[1] Logan N, Graham A, Zhao X, Fisher R, Maiti B, Leone G, La Thangue NB. E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7. Oncogene. 2005 Jul 21;24(31):5000-4. PMID:15897886 doi:http://dx.doi.org/10.1038/sj.onc.1208703

[2] Christensen J, Cloos P, Toftegaard U, Klinkenberg D, Bracken AP, Trinh E, Heeran M, Di Stefano L, Helin K. Characterization of E2F8, a novel E2F-like cell-cycle regulated repressor of E2F-activated transcription. Nucleic Acids Res. 2005 Sep 22;33(17):5458-70. Print 2005. PMID:16179649 doi:http://dx.doi.org/10.1093/nar/gki855

[3] Zalmas LP, Zhao X, Graham AL, Fisher R, Reilly C, Coutts AS, La Thangue NB. DNA-damage response control of E2F7 and E2F8. EMBO Rep. 2008 Mar;9(3):252-9. doi: 10.1038/sj.embor.7401158. Epub 2008 Jan 18. PMID:18202719 doi:http://dx.doi.org/10.1038/sj.embor.7401158

[4] Weijts BG, Bakker WJ, Cornelissen PW, Liang KH, Schaftenaar FH, Westendorp B, de Wolf CA, Paciejewska M, Scheele CL, Kent L, Leone G, Schulte-Merker S, de Bruin A. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J. 2012 Oct 3;31(19):3871-84. doi: 10.1038/emboj.2012.231. Epub 2012 Aug 17. PMID:22903062 doi:http://dx.doi.org/10.1038/emboj.2012.231

[5] Morgunova E, Yin Y, Jolma A, Dave K, Schmierer B, Popov A, Eremina N, Nilsson L, Taipale J. Structural insights into the DNA-binding specificity of E2F family transcription factors. Nat Commun. 2015 Dec 3;6:10050. doi: 10.1038/ncomms10050. PMID:26632596 doi:http://dx.doi.org/10.1038/ncomms10050

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