6irr

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Solution structure of DISC1/ATF4 complexSolution structure of DISC1/ATF4 complex

Structural highlights

6irr is a 1 chain structure with sequence from Mus musculus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ATF4_MOUSE Transcription factor that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress response (ISR) (PubMed:8506317, PubMed:11106749, PubMed:12667446, PubMed:23624402). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer (PubMed:8506317, PubMed:23624402). Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress (PubMed:11106749, PubMed:12667446). During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery (PubMed:11106749, PubMed:12667446). Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation (PubMed:12667446). Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (By similarity). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress (PubMed:15775988, PubMed:21159964). However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (By similarity). Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved (PubMed:23624402). Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress (PubMed:15775988, PubMed:17369260, PubMed:21159964). May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (By similarity). In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity (PubMed:10096021, PubMed:10885750, PubMed:11806972, PubMed:12925279, PubMed:15109498, PubMed:22298775). Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix (PubMed:15109498). Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (PubMed:22298775). Activates transcription of SIRT4 (PubMed:23663782). Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4 (PubMed:21768648, PubMed:22572884). Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes (PubMed:21768648, PubMed:22572884). Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory (PubMed:12925279). Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (PubMed:31444471).[UniProtKB:P18848][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] DISC1_MOUSE Involved in the regulation of multiple aspects of embryonic and adult neurogenesis. Required for neural progenitor proliferation in the ventrical/subventrical zone during embryonic brain development and in the adult dentate gyrus of the hippocampus. Participates in the Wnt-mediated neural progenitor proliferation as a positive regulator by modulating GSK3B activity and CTNNB1 abundance. Plays a role as a modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including neuron positioning, dendritic development and synapse formation. Inhibits the activation of AKT-mTOR signaling upon interaction with CCDC88A. Regulates the migration of early-born granule cell precursors toward the dentate gyrus during the hippocampal development. Plays a role, together with PCNT, in the microtubule network formation.[18] [19] [20] [21]

Publication Abstract from PubMed

Psychiatric disorders are a collection of heterogeneous mental disorders arising from a contribution of genetic and environmental insults, many of which molecularly converge on transcriptional dysregulation, resulting in altered synaptic functions. The underlying mechanisms linking the genetic lesion and functional phenotypes remain largely unknown. Patient iPSC-derived neurons with a rare frameshift DISC1 (Disrupted-in-schizophrenia 1) mutation have previously been shown to exhibit aberrant gene expression and deficits in synaptic functions. How DISC1 regulates gene expression is largely unknown. Here we show that Activating Transcription Factor 4 (ATF4), a DISC1 binding partner, is more abundant in the nucleus of DISC1 mutant human neurons and exhibits enhanced binding to a collection of dysregulated genes. Functionally, overexpressing ATF4 in control neurons recapitulates deficits seen in DISC1 mutant neurons, whereas transcriptional and synaptic deficits are rescued in DISC1 mutant neurons with CRISPR-mediated heterozygous ATF4 knockout. By solving the high-resolution atomic structure of the DISC1-ATF4 complex, we show that mechanistically, the mutation of DISC1 disrupts normal DISC1-ATF4 interaction, and results in excessive ATF4 binding to DNA targets and deregulated gene expression. Together, our study identifies the molecular and structural basis of an DISC1-ATF4 interaction underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.

Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.,Wang X, Ye F, Wen Z, Guo Z, Yu C, Huang WK, Rojas Ringeling F, Su Y, Zheng W, Zhou G, Christian KM, Song H, Zhang M, Ming GL Mol Psychiatry. 2021 Apr;26(4):1346-1360. doi: 10.1038/s41380-019-0485-2. Epub , 2019 Aug 23. PMID:31444471[22]

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

References

  1. ↑ Tanaka T, Tsujimura T, Takeda K, Sugihara A, Maekawa A, Terada N, Yoshida N, Akira S. Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells. 1998 Dec;3(12):801-10. PMID:10096021 doi:10.1046/j.1365-2443.1998.00230.x
  2. ↑ Hettmann T, Barton K, Leiden JM. Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor. Dev Biol. 2000 Jun 1;222(1):110-23. PMID:10885750 doi:10.1006/dbio.2000.9699
  3. ↑ Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000 Nov;6(5):1099-108. PMID:11106749 doi:10.1016/s1097-2765(00)00108-8
  4. ↑ Masuoka HC, Townes TM. Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood. 2002 Feb 1;99(3):736-45. PMID:11806972 doi:10.1182/blood.v99.3.736
  5. ↑ Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003 Mar;11(3):619-33. PMID:12667446 doi:10.1016/s1097-2765(03)00105-9
  6. ↑ Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, Gilliam TC, Kandel ER. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron. 2003 Aug 14;39(4):655-69. PMID:12925279 doi:10.1016/s0896-6273(03)00501-4
  7. ↑ Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, Hanauer A, Karsenty G. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 2004 Apr 30;117(3):387-98. PMID:15109498 doi:10.1016/s0092-8674(04)00344-7
  8. ↑ Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J. 2005 Mar 23;24(6):1243-55. Epub 2005 Mar 10. PMID:15775988 doi:http://dx.doi.org/10.1038/sj.emboj.7600596
  9. ↑ Jousse C, Deval C, Maurin AC, Parry L, Chérasse Y, Chaveroux C, Lefloch R, Lenormand P, Bruhat A, Fafournoux P. TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway. J Biol Chem. 2007 May 25;282(21):15851-61. PMID:17369260 doi:10.1074/jbc.M611723200
  10. ↑ Galehdar Z, Swan P, Fuerth B, Callaghan SM, Park DS, Cregan SP. Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA. J Neurosci. 2010 Dec 15;30(50):16938-48. doi: 10.1523/JNEUROSCI.1598-10.2010. PMID:21159964 doi:http://dx.doi.org/10.1523/JNEUROSCI.1598-10.2010
  11. ↑ Koyanagi S, Hamdan AM, Horiguchi M, Kusunose N, Okamoto A, Matsunaga N, Ohdo S. cAMP-response element (CRE)-mediated transcription by activating transcription factor-4 (ATF4) is essential for circadian expression of the Period2 gene. J Biol Chem. 2011 Sep 16;286(37):32416-23. doi: 10.1074/jbc.M111.258970. Epub, 2011 Jul 18. PMID:21768648 doi:http://dx.doi.org/10.1074/jbc.M111.258970
  12. ↑ Kode A, Mosialou I, Silva BC, Joshi S, Ferron M, Rached MT, Kousteni S. FoxO1 protein cooperates with ATF4 protein in osteoblasts to control glucose homeostasis. J Biol Chem. 2012 Mar 16;287(12):8757-68. PMID:22298775 doi:10.1074/jbc.M111.282897
  13. ↑ Ushijima K, Koyanagi S, Sato Y, Ogata T, Matsunaga N, Fujimura A, Ohdo S. Role of activating transcription factor-4 in 24-hour rhythm of serotonin transporter expression in the mouse midbrain. Mol Pharmacol. 2012 Aug;82(2):264-70. PMID:22572884 doi:10.1124/mol.112.079079
  14. ↑ Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013 May;15(5):481-90. PMID:23624402 doi:10.1038/ncb2738
  15. ↑ Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 2013 May 9;153(4):840-54. PMID:23663782 doi:10.1016/j.cell.2013.04.023
  16. ↑ Wang X, Ye F, Wen Z, Guo Z, Yu C, Huang WK, Rojas Ringeling F, Su Y, Zheng W, Zhou G, Christian KM, Song H, Zhang M, Ming GL. Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders. Mol Psychiatry. 2021 Apr;26(4):1346-1360. PMID:31444471 doi:10.1038/s41380-019-0485-2
  17. ↑ Vallejo M, Ron D, Miller CP, Habener JF. C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4679-83. PMID:8506317 doi:10.1073/pnas.90.10.4679
  18. ↑ Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Epub 2007 Sep 6. PMID:17825401 doi:http://dx.doi.org/10.1016/j.cell.2007.07.010
  19. ↑ Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009 Mar 20;136(6):1017-31. doi: 10.1016/j.cell.2008.12.044. PMID:19303846 doi:http://dx.doi.org/10.1016/j.cell.2008.12.044
  20. ↑ Meyer KD, Morris JA. Disc1 regulates granule cell migration in the developing hippocampus. Hum Mol Genet. 2009 Sep 1;18(17):3286-97. doi: 10.1093/hmg/ddp266. Epub 2009 Jun , 5. PMID:19502360 doi:http://dx.doi.org/10.1093/hmg/ddp266
  21. ↑ Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N, Kang E, Song H, Ming GL. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009 Sep 24;63(6):761-73. doi: 10.1016/j.neuron.2009.08.008. PMID:19778506 doi:http://dx.doi.org/10.1016/j.neuron.2009.08.008
  22. ↑ Wang X, Ye F, Wen Z, Guo Z, Yu C, Huang WK, Rojas Ringeling F, Su Y, Zheng W, Zhou G, Christian KM, Song H, Zhang M, Ming GL. Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders. Mol Psychiatry. 2021 Apr;26(4):1346-1360. PMID:31444471 doi:10.1038/s41380-019-0485-2
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