6qnx

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Structure of the SA2/SCC1/CTCF complexStructure of the SA2/SCC1/CTCF complex

Structural highlights

6qnx is a 3 chain structure with sequence from Human. This structure supersedes the now removed PDB entry 6qny. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:STAG2, SA2 (HUMAN), RAD21, HR21, KIAA0078, NXP1, SCC1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[RAD21_HUMAN] Cornelia de Lange syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1]

Function

[STAG2_HUMAN] Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.[2] [CTCF_HUMAN] Chromatin binding factor that binds to DNA sequence specific sites. Involved in transcriptional regulation by binding to chromatin insulators and preventing interaction between promoter and nearby enhancers and silencers. Acts as transcriptional repressor binding to promoters of vertebrate MYC gene and BAG1 gene. Also binds to the PLK and PIM1 promoters. Acts as a transcriptional activator of APP. Regulates APOA1/C3/A4/A5 gene cluster and controls MHC class II gene expression. Plays an essential role in oocyte and preimplantation embryo development by activating or repressing transcription. Seems to act as tumor suppressor. Plays a critical role in the epigenetic regulation. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, binding within the H19 imprinting control region (ICR) mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to IGF2. Plays a critical role in gene silencing over considerable distances in the genome. Preferentially interacts with unmethylated DNA, preventing spreading of CpG methylation and maintaining methylation-free zones. Inversely, binding to target sites is prevented by CpG methylation. Plays a important role in chromatin remodeling. Can dimerize when it is bound to different DNA sequences, mediating long-range chromatin looping. Mediates interchromosomal association between IGF2/H19 and WSB1/NF1 and may direct distant DNA segments to a common transcription factory. Causes local loss of histone acetylation and gain of histone methylation in the beta-globin locus, without affecting transcription. When bound to chromatin, it provides an anchor point for nucleosomes positioning. Seems to be essential for homologous X-chromosome pairing. May participate with Tsix in establishing a regulatable epigenetic switch for X chromosome inactivation. May play a role in preventing the propagation of stable methylation at the escape genes from X- inactivation. Involved in sister chromatid cohesion. Associates with both centromeres and chromosomal arms during metaphase and required for cohesin localization to CTCF sites. Regulates asynchronous replication of IGF2/H19.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [RAD21_HUMAN] Cleavable component of the cohesin complex, involved in chromosome cohesion during cell cycle, in DNA repair, and in apoptosis. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At metaphase-anaphase transition, this protein is cleaved by separase/ESPL1 and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Also plays a role in apoptosis, via its cleavage by caspase-3/CASP3 or caspase-7/CASP7 during early steps of apoptosis: the C-terminal 64 kDa cleavage product may act as a nuclear signal to initiate cytoplasmic events involved in the apoptotic pathway.[13] [14]

Publication Abstract from PubMed

Cohesin catalyses the folding of the genome into loops that are anchored by CTCF(1). The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2-SCC1 subunits of cohesin. A 2.6 A crystal structure of SA2-SCC1 in complex with CTCF reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF-binding sites. A similar motif is present in a number of established and novel cohesin ligands, including the cohesin release factor WAPL(2,3). Our data suggest that CTCF enables chromatin loop formation by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables dynamic regulation of chromatin folding by cohesin and CTCF.

The structural basis for cohesin-CTCF-anchored loops.,Li Y, Haarhuis JHI, Cacciatore AS, Oldenkamp R, van Ruiten MS, Willems L, Teunissen H, Muir KW, de Wit E, Rowland BD, Panne D Nature. 2020 Jan 6. pii: 10.1038/s41586-019-1910-z. doi:, 10.1038/s41586-019-1910-z. PMID:31905366[15]

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

References

  1. ↑ Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, Monnich M, Yan Y, Xu W, Gil-Rodriguez MC, Clark D, Hakonarson H, Halbach S, Michelis LD, Rampuria A, Rossier E, Spranger S, Van Maldergem L, Lynch SA, Gillessen-Kaesbach G, Ludecke HJ, Ramsay RG, McKay MJ, Krantz ID, Xu H, Horsfield JA, Kaiser FJ. RAD21 mutations cause a human cohesinopathy. Am J Hum Genet. 2012 Jun 8;90(6):1014-27. doi: 10.1016/j.ajhg.2012.04.019. Epub, 2012 May 24. PMID:22633399 doi:http://dx.doi.org/10.1016/j.ajhg.2012.04.019
  2. ↑ Prieto I, Pezzi N, Buesa JM, Kremer L, Barthelemy I, Carreiro C, Roncal F, Martinez A, Gomez L, Fernandez R, Martinez-A C, Barbero JL. STAG2 and Rad21 mammalian mitotic cohesins are implicated in meiosis. EMBO Rep. 2002 Jun;3(6):543-50. Epub 2002 May 24. PMID:12034751 doi:http://dx.doi.org/10.1093/embo-reports/kvf108
  3. ↑ Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV. An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol. 1996 Jun;16(6):2802-13. PMID:8649389
  4. ↑ Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV. A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. Genes Chromosomes Cancer. 1998 May;22(1):26-36. PMID:9591631
  5. ↑ Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 2002 Jan 11;295(5553):345-7. Epub 2001 Dec 6. PMID:11743158 doi:http://dx.doi.org/10.1126/science.1065982
  6. ↑ Kurukuti S, Tiwari VK, Tavoosidana G, Pugacheva E, Murrell A, Zhao Z, Lobanenkov V, Reik W, Ohlsson R. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10684-9. Epub 2006 Jun 30. PMID:16815976 doi:http://dx.doi.org/0600326103
  7. ↑ Renda M, Baglivo I, Burgess-Beusse B, Esposito S, Fattorusso R, Felsenfeld G, Pedone PV. Critical DNA binding interactions of the insulator protein CTCF: a small number of zinc fingers mediate strong binding, and a single finger-DNA interaction controls binding at imprinted loci. J Biol Chem. 2007 Nov 16;282(46):33336-45. Epub 2007 Sep 7. PMID:17827499 doi:http://dx.doi.org/M706213200
  8. ↑ Sun L, Huang L, Nguyen P, Bisht KS, Bar-Sela G, Ho AS, Bradbury CM, Yu W, Cui H, Lee S, Trepel JB, Feinberg AP, Gius D. DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation. Cancer Res. 2008 Apr 15;68(8):2726-35. PMID:18413740 doi:68/8/2726
  9. ↑ Majumder P, Gomez JA, Chadwick BP, Boss JM. The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. J Exp Med. 2008 Apr 14;205(4):785-98. Epub 2008 Mar 17. PMID:18347100 doi:http://dx.doi.org/jem.20071843
  10. ↑ Fu Y, Sinha M, Peterson CL, Weng Z. The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome. PLoS Genet. 2008 Jul 25;4(7):e1000138. PMID:18654629 doi:http://dx.doi.org/10.1371/journal.pgen.1000138
  11. ↑ Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A. CTCF physically links cohesin to chromatin. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8309-14. Epub 2008 Jun 11. PMID:18550811 doi:http://dx.doi.org/0801273105
  12. ↑ Mishiro T, Ishihara K, Hino S, Tsutsumi S, Aburatani H, Shirahige K, Kinoshita Y, Nakao M. Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster. EMBO J. 2009 May 6;28(9):1234-45. Epub 2009 Mar 26. PMID:19322193 doi:http://dx.doi.org/emboj200981
  13. ↑ Pati D, Zhang N, Plon SE. Linking sister chromatid cohesion and apoptosis: role of Rad21. Mol Cell Biol. 2002 Dec;22(23):8267-77. PMID:12417729
  14. ↑ Chen F, Kamradt M, Mulcahy M, Byun Y, Xu H, McKay MJ, Cryns VL. Caspase proteolysis of the cohesin component RAD21 promotes apoptosis. J Biol Chem. 2002 May 10;277(19):16775-81. Epub 2002 Mar 1. PMID:11875078 doi:http://dx.doi.org/10.1074/jbc.M201322200
  15. ↑ Li Y, Haarhuis JHI, Cacciatore AS, Oldenkamp R, van Ruiten MS, Willems L, Teunissen H, Muir KW, de Wit E, Rowland BD, Panne D. The structural basis for cohesin-CTCF-anchored loops. Nature. 2020 Jan 6. pii: 10.1038/s41586-019-1910-z. doi:, 10.1038/s41586-019-1910-z. PMID:31905366 doi:http://dx.doi.org/10.1038/s41586-019-1910-z

6qnx, resolution 2.70Å

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