6r6g

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Structure of XBP1u-paused ribosome nascent chain complex with SRP.

Structural highlights

6r6g is a 91 chain structure with sequence from Canis lupus familiaris, Human, Homo sapiens, Oryctolagus cuniculus and Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:XBP1, TREB5, XBP2 (HUMAN)
Experimental data:Check to display Experimental Data
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[XBP1_HUMAN] Disease susceptibility may be associated with variations affecting the gene represented in this entry.

Function

[F1Q0Z5_CANLF] Signal-recognition-particle assembly has a crucial role in targeting secretory proteins to the rough endoplasmic reticulum membrane. SRP9 together with SRP14 and the Alu portion of the SRP RNA, constitutes the elongation arrest domain of SRP. The complex of SRP9 and SRP14 is required for SRP RNA binding.[PIRNR:PIRNR017029] [G1SS70_RABIT] May play a role during erythropoiesis through regulation of transcription factor DDIT3.[HAMAP-Rule:MF_03122] [SRP14_CANLF] Signal-recognition-particle assembly has a crucial role in targeting secretory proteins to the rough endoplasmic reticulum membrane. SRP9 together with SRP14 and the Alu portion of the SRP RNA, constitutes the elongation arrest domain of SRP. The complex of SRP9 and SRP14 is required for SRP RNA binding. [SRP54_CANLF] Binds to the signal sequence of presecretory protein when they emerge from the ribosomes and transfers them to TRAM (translocating chain-associating membrane protein). [XBP1_HUMAN] Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland (By similarity). Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins (PubMed:11460154). Modulates the cellular response to ER stress in a PIK3R-dependent manner (PubMed:20348923). Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes (PubMed:8349596). Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Functions also as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention (By similarity).[UniProtKB:O35426][1] [2] [3] Isoform 1: Plays a role in the unconventional cytoplasmic splicing processing of its own mRNA triggered by the endoplasmic reticulum (ER) transmembrane endoribonuclease ENR1: upon ER stress, the emerging XBP1 polypeptide chain, as part of a mRNA-ribosome-nascent chain (R-RNC) complex, cotranslationally recruits its own unprocessed mRNA through transient docking to the ER membrane and translational pausing, therefore facilitating efficient IRE1-mediated XBP1 mRNA isoform 2 production (PubMed:19394296, PubMed:21233347). In endothelial cells (EC), associated with KDR, promotes IRE1-mediated XBP1 mRNA isoform 2 productions in a vascular endothelial growth factor (VEGF)-dependent manner, leading to EC proliferation and angiogenesis (PubMed:23529610). Functions as a negative feed-back regulator of the potent transcription factor XBP1 isoform 2 protein levels through proteasome-mediated degradation, thus preventing the constitutive activation of the ER stress response signaling pathway (PubMed:16461360, PubMed:25239945). Inhibits the transactivation activity of XBP1 isoform 2 in myeloma cells (By similarity). Acts as a weak transcriptional factor (PubMed:8657566). Together with HDAC3, contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to EC survival under disturbed flow/oxidative stress (PubMed:25190803). Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464). Binds to the consensus 5'-GATGACGTG[TG]N(3)[AT]T-3' sequence related to cAMP responsive element (CRE)-like sequences (PubMed:8657566). Binds the Tax-responsive element (TRE) present in the long terminal repeat (LTR) of T-cell leukemia virus type 1 (HTLV-I) and to the TPA response elements (TRE) (PubMed:2321018, PubMed:2196176, PubMed:1903538, PubMed:8657566). Associates preferentially to the HDAC3 gene promoter region in a static flow-dependent manner (PubMed:25190803). Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856).[UniProtKB:O35426][4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] Isoform 2: Functions as a stress-inducible potent transcriptional activator during endoplasmic reticulum (ER) stress by inducing unfolded protein response (UPR) target genes via binding to the UPR element (UPRE). Up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanism, respectively, in order to maintain the homeostasis of the ER under ER stress (PubMed:11779464, PubMed:25239945). Plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation (By similarity). Induces phospholipid biosynthesis and ER expansion (PubMed:15466483). Contributes to the VEGF-induced endothelial cell (EC) growth and proliferation in a Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression (PubMed:23529610). Promotes umbilical vein EC apoptosis and atherosclerotisis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions (PubMed:19416856, PubMed:23529610). Involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation (PubMed:23184933). Plays a role as an oncogene by promoting tumor progression: stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells (PubMed:25280941). Involved in adipocyte differentiation by regulating lipogenic gene expression during lactation. Plays a role in the survival of both dopaminergic neurons of the substantia nigra pars compacta (SNpc), by maintaining protein homeostasis and of myeloma cells. Increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. Improves also glucose homeostasis in an ER stress- and/or insulin-independent manner through both binding and proteasome-induced degradation of the transcription factor FOXO1, hence resulting in suppression of gluconeogenic genes expression and in a reduction of blood glucose levels. Controls the induction of de novo fatty acid synthesis in hepatocytes by regulating the expression of a subset of lipogenic genes in an ER stress- and UPR-independent manner (By similarity). Associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner (PubMed:25190803). Binds to the BECN1 gene promoter region (PubMed:23184933). Binds to the CDH5/VE-cadherin gene promoter region (PubMed:19416856). Binds to the ER stress response element (ERSE) upon ER stress (PubMed:11779464). Binds to the 5'-CCACG-3' motif in the PPARG promoter (By similarity).[UniProtKB:O35426][16] [17] [18] [19] [20] [21] [22] [23] [U3KPD5_RABIT] Binds to the 23S rRNA.[RuleBase:RU000576]

Publication Abstract from PubMed

XBP1u, a central component of the unfolded protein response (UPR), is a mammalian protein containing a functionally critical translational arrest peptide (AP). Here, we present a 3 A cryo-EM structure of the stalled human XBP1u AP. It forms a unique turn in the ribosomal exit tunnel proximal to the peptidyl transferase center where it causes a subtle distortion, thereby explaining the temporary translational arrest induced by XBP1u. During ribosomal pausing the hydrophobic region 2 (HR2) of XBP1u is recognized by SRP, but fails to efficiently gate the Sec61 translocon. An exhaustive mutagenesis scan of the XBP1u AP revealed that only 8 out of 20 mutagenized positions are optimal; in the remaining 12 positions, we identify 55 different mutations increase the level of translational arrest. Thus, the wildtype XBP1u AP induces only an intermediate level of translational arrest, allowing efficient targeting by SRP without activating the Sec61 channel.

Structural and mutational analysis of the ribosome-arresting human XBP1u.,Shanmuganathan V, Schiller N, Magoulopoulou A, Cheng J, Braunger K, Cymer F, Berninghausen O, Beatrix B, Kohno K, Heijne GV, Beckmann R Elife. 2019 Jun 27;8. pii: 46267. doi: 10.7554/eLife.46267. PMID:31246176[24]

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

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See Also

References

  1. ↑ Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001 Jul 19;412(6844):300-7. doi: 10.1038/35085509. PMID:11460154 doi:http://dx.doi.org/10.1038/35085509
  2. ↑ Winnay JN, Boucher J, Mori MA, Ueki K, Kahn CR. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response. Nat Med. 2010 Apr;16(4):438-45. doi: 10.1038/nm.2121. Epub 2010 Mar 28. PMID:20348923 doi:http://dx.doi.org/10.1038/nm.2121
  3. ↑ Ponath PD, Fass D, Liou HC, Glimcher LH, Strominger JL. The regulatory gene, hXBP-1, and its target, HLA-DRA, utilize both common and distinct regulatory elements and protein complexes. J Biol Chem. 1993 Aug 15;268(23):17074-82. PMID:8349596
  4. ↑ Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001 Dec 28;107(7):881-91. PMID:11779464
  5. ↑ Yoshida H, Oku M, Suzuki M, Mori K. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. J Cell Biol. 2006 Feb 13;172(4):565-75. doi: 10.1083/jcb.200508145. Epub 2006 Feb, 6. PMID:16461360 doi:http://dx.doi.org/10.1083/jcb.200508145
  6. ↑ Ono SJ, Liou HC, Davidon R, Strominger JL, Glimcher LH. Human X-box-binding protein 1 is required for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4309-12. doi:, 10.1073/pnas.88.10.4309. PMID:1903538 doi:http://dx.doi.org/10.1073/pnas.88.10.4309
  7. ↑ Yanagitani K, Imagawa Y, Iwawaki T, Hosoda A, Saito M, Kimata Y, Kohno K. Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA. Mol Cell. 2009 Apr 24;34(2):191-200. doi: 10.1016/j.molcel.2009.02.033. PMID:19394296 doi:http://dx.doi.org/10.1016/j.molcel.2009.02.033
  8. ↑ Zeng L, Zampetaki A, Margariti A, Pepe AE, Alam S, Martin D, Xiao Q, Wang W, Jin ZG, Cockerill G, Mori K, Li YS, Hu Y, Chien S, Xu Q. Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8326-31. doi:, 10.1073/pnas.0903197106. Epub 2009 May 1. PMID:19416856 doi:http://dx.doi.org/10.1073/pnas.0903197106
  9. ↑ Yanagitani K, Kimata Y, Kadokura H, Kohno K. Translational pausing ensures membrane targeting and cytoplasmic splicing of XBP1u mRNA. Science. 2011 Feb 4;331(6017):586-9. doi: 10.1126/science.1197142. Epub 2011 Jan , 13. PMID:21233347 doi:http://dx.doi.org/10.1126/science.1197142
  10. ↑ Yoshimura T, Fujisawa J, Yoshida M. Multiple cDNA clones encoding nuclear proteins that bind to the tax-dependent enhancer of HTLV-1: all contain a leucine zipper structure and basic amino acid domain. EMBO J. 1990 Aug;9(8):2537-42. PMID:2196176
  11. ↑ Liou HC, Boothby MR, Finn PW, Davidon R, Nabavi N, Zeleznik-Le NJ, Ting JP, Glimcher LH. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science. 1990 Mar 30;247(4950):1581-4. PMID:2321018
  12. ↑ Zeng L, Xiao Q, Chen M, Margariti A, Martin D, Ivetic A, Xu H, Mason J, Wang W, Cockerill G, Mori K, Li JY, Chien S, Hu Y, Xu Q. Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation. 2013 Apr 23;127(16):1712-22. doi: 10.1161/CIRCULATIONAHA.112.001337., Epub 2013 Mar 25. PMID:23529610 doi:http://dx.doi.org/10.1161/CIRCULATIONAHA.112.001337
  13. ↑ Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, Yu H, Zampetaki A, Hu Y, Xu Q, Zeng L. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3. J Biol Chem. 2014 Oct 31;289(44):30625-34. doi: 10.1074/jbc.M114.571984. Epub, 2014 Sep 4. PMID:25190803 doi:http://dx.doi.org/10.1074/jbc.M114.571984
  14. ↑ Chen CY, Malchus NS, Hehn B, Stelzer W, Avci D, Langosch D, Lemberg MK. Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u. EMBO J. 2014 Nov 3;33(21):2492-506. doi: 10.15252/embj.201488208. Epub 2014 Sep, 19. PMID:25239945 doi:http://dx.doi.org/10.15252/embj.201488208
  15. ↑ Clauss IM, Chu M, Zhao JL, Glimcher LH. The basic domain/leucine zipper protein hXBP-1 preferentially binds to and transactivates CRE-like sequences containing an ACGT core. Nucleic Acids Res. 1996 May 15;24(10):1855-64. PMID:8657566
  16. ↑ Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001 Dec 28;107(7):881-91. PMID:11779464
  17. ↑ Sriburi R, Jackowski S, Mori K, Brewer JW. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol. 2004 Oct 11;167(1):35-41. doi: 10.1083/jcb.200406136. Epub 2004 Oct , 4. PMID:15466483 doi:http://dx.doi.org/10.1083/jcb.200406136
  18. ↑ Zeng L, Zampetaki A, Margariti A, Pepe AE, Alam S, Martin D, Xiao Q, Wang W, Jin ZG, Cockerill G, Mori K, Li YS, Hu Y, Chien S, Xu Q. Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8326-31. doi:, 10.1073/pnas.0903197106. Epub 2009 May 1. PMID:19416856 doi:http://dx.doi.org/10.1073/pnas.0903197106
  19. ↑ Margariti A, Li H, Chen T, Martin D, Vizcay-Barrena G, Alam S, Karamariti E, Xiao Q, Zampetaki A, Zhang Z, Wang W, Jiang Z, Gao C, Ma B, Chen YG, Cockerill G, Hu Y, Xu Q, Zeng L. XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J Biol Chem. 2013 Jan 11;288(2):859-72. doi: 10.1074/jbc.M112.412783. Epub 2012, Nov 26. PMID:23184933 doi:http://dx.doi.org/10.1074/jbc.M112.412783
  20. ↑ Zeng L, Xiao Q, Chen M, Margariti A, Martin D, Ivetic A, Xu H, Mason J, Wang W, Cockerill G, Mori K, Li JY, Chien S, Hu Y, Xu Q. Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation. 2013 Apr 23;127(16):1712-22. doi: 10.1161/CIRCULATIONAHA.112.001337., Epub 2013 Mar 25. PMID:23529610 doi:http://dx.doi.org/10.1161/CIRCULATIONAHA.112.001337
  21. ↑ Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, Yu H, Zampetaki A, Hu Y, Xu Q, Zeng L. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3. J Biol Chem. 2014 Oct 31;289(44):30625-34. doi: 10.1074/jbc.M114.571984. Epub, 2014 Sep 4. PMID:25190803 doi:http://dx.doi.org/10.1074/jbc.M114.571984
  22. ↑ Chen CY, Malchus NS, Hehn B, Stelzer W, Avci D, Langosch D, Lemberg MK. Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u. EMBO J. 2014 Nov 3;33(21):2492-506. doi: 10.15252/embj.201488208. Epub 2014 Sep, 19. PMID:25239945 doi:http://dx.doi.org/10.15252/embj.201488208
  23. ↑ Li H, Chen X, Gao Y, Wu J, Zeng F, Song F. XBP1 induces snail expression to promote epithelial- to-mesenchymal transition and invasion of breast cancer cells. Cell Signal. 2015 Jan;27(1):82-9. doi: 10.1016/j.cellsig.2014.09.018. Epub 2014, Oct 2. PMID:25280941 doi:http://dx.doi.org/10.1016/j.cellsig.2014.09.018
  24. ↑ Shanmuganathan V, Schiller N, Magoulopoulou A, Cheng J, Braunger K, Cymer F, Berninghausen O, Beatrix B, Kohno K, Heijne GV, Beckmann R. Structural and mutational analysis of the ribosome-arresting human XBP1u. Elife. 2019 Jun 27;8. pii: 46267. doi: 10.7554/eLife.46267. PMID:31246176 doi:http://dx.doi.org/10.7554/eLife.46267

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6r6g, resolution 3.70Å

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