| Structural highlights
6wg3 is a 7 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Gene: | SMC1A, DXS423E, KIAA0178, SB1.8, SMC1, SMC1L1 (HUMAN), SMC3, BAM, BMH, CSPG6, SMC3L1 (HUMAN), RAD21, HR21, KIAA0078, NXP1, SCC1 (HUMAN), STAG1, SA1, SCC3 (HUMAN), NIPBL, IDN3, SCC2 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[STAG1_HUMAN] STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome. The disease is caused by mutations affecting the gene represented in this entry. [SMC1A_HUMAN] Cornelia de Lange syndrome;Wiedemann-Steiner syndrome. The disease is caused by mutations affecting the gene represented in this entry. [RAD21_HUMAN] Cornelia de Lange syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1] [SMC3_HUMAN] Cornelia de Lange syndrome. The disease is caused by mutations affecting the gene represented in this entry. [NIPBL_HUMAN] Cornelia de Lange syndrome;5p13 microduplication syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
[STAG1_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. [SMC1A_HUMAN] Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. 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 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. Involved in DNA repair via its interaction with BRCA1 and its related phosphorylation by ATM, or via its phosphorylation by ATR. Works as a downstream effector both in the ATM/NBS1 branch and in the ATR/MSH2 branch of S-phase checkpoint.[2] [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.[3] [4] [SMC3_HUMAN] Central component of cohesin, a complex required for chromosome cohesion during the cell cycle. The cohesin complex may form 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. Cohesion is coupled to DNA replication and is involved in DNA repair. The cohesin complex plays also an important role in spindle pole assembly during mitosis and in chromosomes movement.[5] [6] [NIPBL_HUMAN] Plays an important role in the loading of the cohesin complex on to DNA. Forms a heterodimeric complex (also known as cohesin loading complex) with MAU2/SCC4 which mediates the loading of the cohesin complex onto chromatin (PubMed:22628566, PubMed:28914604). Plays a role in cohesin loading at sites of DNA damage. Its recruitment to double-strand breaks (DSBs) sites occurs in a CBX3-, RNF8- and RNF168-dependent manner whereas its recruitment to UV irradiation-induced DNA damage sites occurs in a ATM-, ATR-, RNF8- and RNF168-dependent manner (PubMed:28167679). Along with ZNF609, promotes cortical neuron migration during brain development by regulating the transcription of crucial genes in this process. Preferentially binds promoters containing paused RNA polymerase II. Up-regulates the expression of SEMA3A, NRP1, PLXND1 and GABBR2 genes, among others (By similarity).[UniProtKB:Q6KCD5][7] [8] [9]
Publication Abstract from PubMed
As a ring-shaped ATPase machine, cohesin organizes the eukaryotic genome by extruding DNA loops and mediates sister-chromatid cohesion by topologically entrapping DNA. How cohesin executes these fundamental DNA transactions is not understood. Using cryo-electron microscopy, we determine the structure of human cohesin bound to its loader NIPBL and DNA at medium resolution. Cohesin and NIPBL interact extensively and together form a central tunnel to entrap a 72-base pair DNA. NIPBL and DNA promote the engagement of cohesin's ATPase head domains and ATP binding. The hinge domains of cohesin adopt an "open washer" conformation and dock onto the STAG1 subunit. Our structure explains the synergistic activation of cohesin by NIPBL and DNA, and provides insight into DNA entrapment by cohesin.
Cryo-EM structure of the human cohesin-NIPBL-DNA complex.,Shi Z, Gao H, Bai XC, Yu H Science. 2020 May 14. pii: science.abb0981. doi: 10.1126/science.abb0981. PMID:32409525[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ Yazdi PT, Wang Y, Zhao S, Patel N, Lee EY, Qin J. SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. Genes Dev. 2002 Mar 1;16(5):571-82. PMID:11877377 doi:http://dx.doi.org/10.1101/gad.970702
- ↑ 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
- ↑ 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
- ↑ Sumara I, Vorlaufer E, Gieffers C, Peters BH, Peters JM. Characterization of vertebrate cohesin complexes and their regulation in prophase. J Cell Biol. 2000 Nov 13;151(4):749-62. PMID:11076961
- ↑ Terret ME, Sherwood R, Rahman S, Qin J, Jallepalli PV. Cohesin acetylation speeds the replication fork. Nature. 2009 Nov 12;462(7270):231-4. PMID:19907496 doi:nature08550
- ↑ Bermudez VP, Farina A, Higashi TL, Du F, Tappin I, Takahashi TS, Hurwitz J. In vitro loading of human cohesin on DNA by the human Scc2-Scc4 loader complex. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9366-71. doi:, 10.1073/pnas.1206840109. Epub 2012 May 24. PMID:22628566 doi:http://dx.doi.org/10.1073/pnas.1206840109
- ↑ Bot C, Pfeiffer A, Giordano F, Manjeera DE, Dantuma NP, Strom L. Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage. J Cell Sci. 2017 Mar 15;130(6):1134-1146. doi: 10.1242/jcs.197236. Epub 2017 Feb , 6. PMID:28167679 doi:http://dx.doi.org/10.1242/jcs.197236
- ↑ Rhodes J, Mazza D, Nasmyth K, Uphoff S. Scc2/Nipbl hops between chromosomal cohesin rings after loading. Elife. 2017 Sep 15;6. pii: 30000. doi: 10.7554/eLife.30000. PMID:28914604 doi:http://dx.doi.org/10.7554/eLife.30000
- ↑ Shi Z, Gao H, Bai XC, Yu H. Cryo-EM structure of the human cohesin-NIPBL-DNA complex. Science. 2020 May 14. pii: science.abb0981. doi: 10.1126/science.abb0981. PMID:32409525 doi:http://dx.doi.org/10.1126/science.abb0981
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