8b9x

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Chimeric protein of human UFM1 E3 ligase, UFL1, and DDRGK1Chimeric protein of human UFM1 E3 ligase, UFL1, and DDRGK1

Structural highlights

8b9x is a 2 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 3.066Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DDRGK_HUMAN Spondyloepimetaphyseal dysplasia, Shohat type. The disease is caused by variants affecting the gene represented in this entry.

Function

UFL1_HUMAN E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:32160526). In response to endoplasmic reticulum stress, recruited to the endoplasmic reticulum membrane by DDRGK1, and mediates ufmylation of proteins such as RPN1 and RPL26/uL24, thereby promoting reticulophagy of endoplasmic reticulum sheets (PubMed:32160526). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) via ERN1/IRE1-alpha (PubMed:23152784, PubMed:32160526). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:32050156). Regulates inflammation in response to endoplasmic reticulum stress by promoting reticulophagy, leading to inhibit the activity of the NF-kappa-B transcription factor (By similarity). Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is a collateral effect or is required for ufmylation (PubMed:20531390, PubMed:20018847). Catalyzes ufmylation of various subunits of the ribosomal complex or associated components, such as RPS3/uS3, RPS20/uS10, RPL10/uL16, RPL26/uL24 and EIF6 (By similarity). Anchors CDK5RAP3 in the cytoplasm, preventing its translocation to the nucleus which allows expression of the CCND1 cyclin and progression of cells through the G1/S transition (PubMed:20531390). Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 (PubMed:30886146). Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (PubMed:25219498). Required for hematopoietic stem cell function and hematopoiesis (By similarity). Required for cardiac homeostasis (By similarity).[UniProtKB:A1A4I9][UniProtKB:Q8CCJ3][1] [2] [3] [4] [5] [6] [7] [8] [9] DDRGK_HUMAN Substrate adapter for ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, which plays a key role in reticulophagy (also called ER-phagy) (PubMed:32160526). In response to endoplasmic reticulum stress, promotes recruitment of the E3 UFM1-protein ligase UFL1 to the endoplasmic reticulum membrane: in turn, UFL1 mediates ufmylation of proteins such as RPN1 and RPL26/uL24, promoting reticulophagy of endoplasmic reticulum sheets (PubMed:32160526). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) by regulating ERN1/IRE1-alpha stability (PubMed:28128204, PubMed:32160526). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis or inflammatory response (By similarity). Required for TRIP4 ufmylation, thereby regulating nuclear receptors-mediated. transcription (PubMed:25219498). May play a role in NF-kappa-B-mediated transcription through regulation of the phosphorylation and the degradation of NFKBIA, the inhibitor of NF-kappa-B (PubMed:23675531). Plays a role in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator (PubMed:28263186).[UniProtKB:Q80WW9][10] [11] [12] [13] [14]

References

  1. ↑ Tatsumi K, Sou YS, Tada N, Nakamura E, Iemura S, Natsume T, Kang SH, Chung CH, Kasahara M, Kominami E, Yamamoto M, Tanaka K, Komatsu M. A novel type of E3 ligase for the Ufm1 conjugation system. J Biol Chem. 2010 Feb 19;285(8):5417-27. doi: 10.1074/jbc.M109.036814. Epub 2009 , Dec 14. PMID:20018847 doi:http://dx.doi.org/10.1074/jbc.M109.036814
  2. ↑ Kwon J, Cho HJ, Han SH, No JG, Kwon JY, Kim H. A novel LZAP-binding protein, NLBP, inhibits cell invasion. J Biol Chem. 2010 Apr 16;285(16):12232-40. PMID:20164180 doi:10.1074/jbc.M109.065920
  3. ↑ Wu J, Lei G, Mei M, Tang Y, Li H. A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing Protein 1 (DDRGK1) and modulates NF-kappaB signaling. J Biol Chem. 2010 May 14;285(20):15126-15136. PMID:20228063 doi:10.1074/jbc.M110.110619
  4. ↑ Shiwaku H, Yoshimura N, Tamura T, Sone M, Ogishima S, Watase K, Tagawa K, Okazawa H. Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity. EMBO J. 2010 Jul 21;29(14):2446-60. PMID:20531390 doi:10.1038/emboj.2010.116
  5. ↑ Zhang Y, Zhang M, Wu J, Lei G, Li H. Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. PLoS One. 2012;7(11):e48587. PMID:23152784 doi:10.1371/journal.pone.0048587
  6. ↑ Yoo HM, Kang SH, Kim JY, Lee JE, Seong MW, Lee SW, Ka SH, Sou YS, Komatsu M, Tanaka K, Lee ST, Noh DY, Baek SH, Jeon YJ, Chung CH. Modification of ASC1 by UFM1 is crucial for ERalpha transactivation and breast cancer development. Mol Cell. 2014 Oct 23;56(2):261-274. doi: 10.1016/j.molcel.2014.08.007. Epub 2014 , Sep 11. PMID:25219498 doi:http://dx.doi.org/10.1016/j.molcel.2014.08.007
  7. ↑ Qin B, Yu J, Nowsheen S, Wang M, Tu X, Liu T, Li H, Wang L, Lou Z. UFL1 promotes histone H4 ufmylation and ATM activation. Nat Commun. 2019 Mar 18;10(1):1242. PMID:30886146 doi:10.1038/s41467-019-09175-0
  8. ↑ Yang G, Wang Y, Chen Y, Huang R. UFL1 attenuates IL-1β-induced inflammatory response in human osteoarthritis chondrocytes. Int Immunopharmacol. 2020 Apr;81:106278. PMID:32050156 doi:10.1016/j.intimp.2020.106278
  9. ↑ Liang JR, Lingeman E, Luong T, Ahmed S, Muhar M, Nguyen T, Olzmann JA, Corn JE. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation. Cell. 2020 Mar 19;180(6):1160-1177.e20. doi: 10.1016/j.cell.2020.02.017. Epub , 2020 Mar 10. PMID:32160526 doi:http://dx.doi.org/10.1016/j.cell.2020.02.017
  10. ↑ Xi P, Ding D, Zhou J, Wang M, Cong YS. DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha stability. PLoS One. 2013 May 10;8(5):e64231. doi: 10.1371/journal.pone.0064231. Print 2013. PMID:23675531 doi:http://dx.doi.org/10.1371/journal.pone.0064231
  11. ↑ Yoo HM, Kang SH, Kim JY, Lee JE, Seong MW, Lee SW, Ka SH, Sou YS, Komatsu M, Tanaka K, Lee ST, Noh DY, Baek SH, Jeon YJ, Chung CH. Modification of ASC1 by UFM1 is crucial for ERalpha transactivation and breast cancer development. Mol Cell. 2014 Oct 23;56(2):261-274. doi: 10.1016/j.molcel.2014.08.007. Epub 2014 , Sep 11. PMID:25219498 doi:http://dx.doi.org/10.1016/j.molcel.2014.08.007
  12. ↑ Liu J, Wang Y, Song L, Zeng L, Yi W, Liu T, Chen H, Wang M, Ju Z, Cong YS. A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1alpha stability. Nat Commun. 2017 Jan 27;8:14186. doi: 10.1038/ncomms14186. PMID:28128204 doi:http://dx.doi.org/10.1038/ncomms14186
  13. ↑ Egunsola AT, Bae Y, Jiang MM, Liu DS, Chen-Evenson Y, Bertin T, Chen S, Lu JT, Nevarez L, Magal N, Raas-Rothschild A, Swindell EC, Cohn DH, Gibbs RA, Campeau PM, Shohat M, Lee BH. Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia. J Clin Invest. 2017 Apr 3;127(4):1475-1484. doi: 10.1172/JCI90193. Epub 2017 Mar , 6. PMID:28263186 doi:http://dx.doi.org/10.1172/JCI90193
  14. ↑ Liang JR, Lingeman E, Luong T, Ahmed S, Muhar M, Nguyen T, Olzmann JA, Corn JE. A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation. Cell. 2020 Mar 19;180(6):1160-1177.e20. doi: 10.1016/j.cell.2020.02.017. Epub , 2020 Mar 10. PMID:32160526 doi:http://dx.doi.org/10.1016/j.cell.2020.02.017

8b9x, resolution 3.07Å

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