UBA1 explained

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene.^{[1] [2]} UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes.^{[1] [3]} This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.^{[4] [5]}

Structure

Gene

The UBA1 gene is located in the chromosome band Xp11.23, consisting of 31 exons.

Protein

The UBA1 for ubiquitin (Ub) is a 110–120 kDa monomeric protein, and the UBA1 for the ubiquitin-like protein (Ubls) NEDD8 and SUMO are heterodimeric complexes with similar molecular weights. All eukaryotic UBA1 contain a two-fold repeat of a domain, derived from the bacterial MoeB and ThiF proteins,^[6] with one occurrence each in the N-terminal and C-terminal half of the UBA1 for Ub, or the separate subunits of the UBA1 for NEDD8 and SUMO.^[7] The UBA1 for Ub consists of four building blocks: First, the adenylation domains composed of two MoeB/ThiF-homology motifs, the latter of which binds ATP and Ub;^{[8] [9] [10]} second, the catalytic cysteine half-domains, which contain the E1 active site cysteine inserted into each of the adenylation domains;^[11] third, a four-helix bundle that represents a second insertion in the inactive adenylation domain and immediately follows the first catalytic cysteine half-domain; and fourth, the C-terminal ubiquitin-fold domain, which recruits specific E2s.^{[12] [13]}

Function

The protein encoded by this gene catalyzes the first step in ubiquitin conjugation, or ubiquitination, to mark cellular proteins for degradation. Specifically, UBA1 catalyzes the ATP-dependent adenylation of ubiquitin, thereby forming a thioester bond between the two. It also continues to participate in subsequent steps of ubiquination as a Ub carrier.^{[4] [5] [14]} There are only two human ubiquitin-activating enzymes, UBA1 and UBA6, and thus UBA1 is largely responsible for protein ubiquitination in humans.^{[4] [5] [14]} Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation.^{[4] [5]} Additionally, UBA1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during stress.^[3]

Clinical significance

Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2.^[1] UBA1 has also been implicated in other neurodegenerative diseases, including spinal muscular atrophy,^[15] as well as cancer and tumors. Since UBA1 is involved in multiple biological processes, there are concerns that inhibiting UBA1 would also damage normal cells. Nonetheless, preclinical testing of a UBA1 inhibitor in mice with leukemia revealed no additional toxic effects to normal cells, and the success of other drugs targeting pleiotropic targets likewise support the safety of using UBA1 inhibitor in cancer treatment^{[4] [5]}

Moreover, the UBA1 inhibitor largazole, as well as its ketone and ester derivatives, preferentially targets cancer over normal cells by specifically blocking the ligation of Ub and UBA1 during the adenylation step of the E1 pathway. MLN4924, a NEDD8-activating enzyme inhibitor functioning according to similar mechanisms, is currently undergoing phase I clinical trials.^[5]

An autoinflammatory condition identified in 2020 and named VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to mutation in methionine41 in UBA1, the E1 enzyme that initiates ubiquitylation.^[16]

Interactions

UBA1 has been shown to interact with:

• UBC13^[4]
• PYR-41^[17]
• himeic acid A^[18]
• hyrtioreticulins A–E^[19]

Further reading

• Nouspikel T, Hanawalt PC . Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme . Proceedings of the National Academy of Sciences of the United States of America . 103 . 44 . 16188–93 . October 2006 . 17060614 . 1621053 . 10.1073/pnas.0607769103 . 2006PNAS..10316188N . free .
• Jin J, Li X, Gygi SP, Harper JW . Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging . Nature . 447 . 7148 . 1135–8 . June 2007 . 17597759 . 10.1038/nature05902 . 2007Natur.447.1135J . 4337767 .
• Xia T, Dimitropoulou C, Zeng J, Antonova GN, Snead C, Venema RC, Fulton D, Qian S, Patterson C, Papapetropoulos A, Catravas JD . Chaperone-dependent E3 ligase CHIP ubiquitinates and mediates proteasomal degradation of soluble guanylyl cyclase . American Journal of Physiology. Heart and Circulatory Physiology . 293 . 5 . H3080–7 . November 2007 . 17873020 . 10.1152/ajpheart.00579.2007 .
• Pridgeon JW, Webber EA, Sha D, Li L, Chin LS . Proteomic analysis reveals Hrs ubiquitin-interacting motif-mediated ubiquitin signaling in multiple cellular processes . The FEBS Journal . 276 . 1 . 118–31 . January 2009 . 19019082 . 2647816 . 10.1111/j.1742-4658.2008.06760.x .
• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP . A probability-based approach for high-throughput protein phosphorylation analysis and site localization . Nature Biotechnology . 24 . 10 . 1285–92 . October 2006 . 16964243 . 10.1038/nbt1240 . 14294292 .
• Malakhova OA, Zhang DE . ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response . The Journal of Biological Chemistry . 283 . 14 . 8783–7 . April 2008 . 18287095 . 2276364 . 10.1074/jbc.C800030200 . free .
• Anindya R, Aygün O, Svejstrup JQ . Damage-induced ubiquitylation of human RNA polymerase II by the ubiquitin ligase Nedd4, but not Cockayne syndrome proteins or BRCA1 . Molecular Cell . 28 . 3 . 386–97 . November 2007 . 17996703 . 10.1016/j.molcel.2007.10.008 . free .
• Umebayashi K, Stenmark H, Yoshimori T . Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation . Molecular Biology of the Cell . 19 . 8 . 3454–62 . August 2008 . 18508924 . 2488299 . 10.1091/mbc.E07-10-0988 .
• Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H . Toward a confocal subcellular atlas of the human proteome . Molecular & Cellular Proteomics . 7 . 3 . 499–508 . March 2008 . 18029348 . 10.1074/mcp.M700325-MCP200 . free .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . free .
• Gallegos JR, Litersky J, Lee H, Sun Y, Nakayama K, Nakayama K, Lu H . SCF TrCP1 activates and ubiquitylates TAp63gamma . The Journal of Biological Chemistry . 283 . 1 . 66–75 . January 2008 . 17965458 . 10.1074/jbc.M704686200 . free .
• Carbia-Nagashima A, Gerez J, Perez-Castro C, Paez-Pereda M, Silberstein S, Stalla GK, Holsboer F, Arzt E . RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia . Cell . 131 . 2 . 309–23 . October 2007 . 17956732 . 10.1016/j.cell.2007.07.044 . 20.500.12110/paper_00928674_v131_n2_p309_CarbiaNagashima . 12486303 . free .
• Ramser J, Ahearn ME, Lenski C, Yariz KO, Hellebrand H, von Rhein M, Clark RD, Schmutzler RK, Lichtner P, Hoffman EP, Meindl A, Baumbach-Reardon L . Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy . American Journal of Human Genetics . 82 . 1 . 188–93 . January 2008 . 18179898 . 2253959 . 10.1016/j.ajhg.2007.09.009 .
• Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, Asahara T, Tokunaga F, Iwai K, Igarashi K . Heme induces ubiquitination and degradation of the transcription factor Bach1 . Molecular and Cellular Biology . 27 . 19 . 6962–71 . October 2007 . 17682061 . 2099246 . 10.1128/MCB.02415-06 .
• Nicassio F, Corrado N, Vissers JH, Areces LB, Bergink S, Marteijn JA, Geverts B, Houtsmuller AB, Vermeulen W, Di Fiore PP, Citterio E . Human USP3 is a chromatin modifier required for S phase progression and genome stability . Current Biology . 17 . 22 . 1972–7 . November 2007 . 17980597 . 10.1016/j.cub.2007.10.034 . free .
• Su ZL, Mo XL, Feng ZY, Lin HL, Ding YG . UBE1 expression in extranodal NK/T cell lymphoma, nasal type . Leukemia & Lymphoma . 49 . 9 . 1821–2 . September 2008 . 18661401 . 10.1080/10428190802187171 . 5481217 .
• Wang X, Shi Y, Wang J, Huang G, Jiang X . Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation . The Biochemical Journal . 414 . 2 . 221–9 . September 2008 . 18498243 . 10.1042/BJ20080674 .
• Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D . Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain . The Biochemical Journal . 415 . 1 . 155–63 . October 2008 . 18498246 . 10.1042/BJ20071708 .
• Zhou W, Zhu P, Wang J, Pascual G, Ohgi KA, Lozach J, Glass CK, Rosenfeld MG . Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation . Molecular Cell . 29 . 1 . 69–80 . January 2008 . 18206970 . 2327256 . 10.1016/j.molcel.2007.11.002 .

Notes and References

1. Web site: Entrez Gene: ubiquitin-like modifier activating enzyme 1.
2. Kudo M, Sugasawa K, Hori T, Enomoto T, Hanaoka F, Ui M . Human ubiquitin-activating enzyme (E1): compensation for heat-labile mouse E1 and its gene localization on the X chromosome . Experimental Cell Research . 192 . 1 . 110–7 . January 1991 . 1845793 . 10.1016/0014-4827(91)90164-P .
3. Leidecker O, Matic I, Mahata B, Pion E, Xirodimas DP . The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions . Cell Cycle . 11 . 6 . 1142–50 . March 2012 . 22370482 . 10.4161/cc.11.6.19559 . free .
4. Correale S, de Paola I, Morgillo CM, Federico A, Zaccaro L, Pallante P, Galeone A, Fusco A, Pedone E, Luque FJ, Catalanotti B . Structural model of the hUbA1-UbcH10 quaternary complex: in silico and experimental analysis of the protein-protein interactions between E1, E2 and ubiquitin . PLOS ONE . 9 . 11 . e112082 . 2014 . 25375166 . 4223017 . 10.1371/journal.pone.0112082 . 2014PLoSO...9k2082C . free .
5. Ungermannova D, Parker SJ, Nasveschuk CG, Wang W, Quade B, Zhang G, Kuchta RD, Phillips AJ, Liu X . Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1) . PLOS ONE . 7 . 1 . e29208 . 2012 . 22279528 . 3261141 . 10.1371/journal.pone.0029208 . 2012PLoSO...729208U . free .
6. Johnson ES, Schwienhorst I, Dohmen RJ, Blobel G . The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer . The EMBO Journal . 16 . 18 . 5509–19 . September 1997 . 9312010 . 10.1093/emboj/16.18.5509 . 1170183.
7. Lee I, Schindelin H . Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes . Cell . 134 . 2 . 268–78 . July 2008 . 18662542 . 10.1016/j.cell.2008.05.046 . free .
8. Lake MW, Wuebbens MM, Rajagopalan KV, Schindelin H . Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex . Nature . 414 . 6861 . 325–9 . November 2001 . 11713534 . 10.1038/35104586 . 2001Natur.414..325L . 3224437 .
9. Lois LM, Lima CD . Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1 . The EMBO Journal . 24 . 3 . 439–51 . February 2005 . 15660128 . 10.1038/sj.emboj.7600552 . 548657.
10. Walden H, Podgorski MS, Schulman BA . Insights into the ubiquitin transfer cascade from the structure of the activating enzyme for NEDD8 . Nature . 422 . 6929 . 330–4 . March 2003 . 12646924 . 10.1038/nature01456 . 2003Natur.422..330W . 4370095 .
11. Szczepanowski RH, Filipek R, Bochtler M . Crystal structure of a fragment of mouse ubiquitin-activating enzyme . The Journal of Biological Chemistry . 280 . 23 . 22006–11 . June 2005 . 15774460 . 10.1074/jbc.M502583200 . free .
12. Huang DT, Paydar A, Zhuang M, Waddell MB, Holton JM, Schulman BA . Structural basis for recruitment of Ubc12 by an E2 binding domain in NEDD8's E1 . Molecular Cell . 17 . 3 . 341–50 . February 2005 . 15694336 . 10.1016/j.molcel.2004.12.020 . free .
13. Huang DT, Hunt HW, Zhuang M, Ohi MD, Holton JM, Schulman BA . Basis for a ubiquitin-like protein thioester switch toggling E1-E2 affinity . Nature . 445 . 7126 . 394–8 . January 2007 . 17220875 . 10.1038/nature05490 . 2821831. 2007Natur.445..394H .
14. Moudry P, Lukas C, Macurek L, Hanzlikova H, Hodny Z, Lukas J, Bartek J . Ubiquitin-activating enzyme UBA1 is required for cellular response to DNA damage . Cell Cycle . 11 . 8 . 1573–82 . April 2012 . 22456334 . 10.4161/cc.19978 . free .
15. 27699224. 10.1172/jci.insight.87908. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI Insight. 1. 11. 2016. Powis. Rachael A.. Karyka. Evangelia. Boyd. Penelope. Côme. Julien. Jones. Ross A.. Zheng. Yinan. Szunyogova. Eva. Groen. Ewout J.N.. Hunter. Gillian. Thomson. Derek. Wishart. Thomas M.. Becker. Catherina G.. Parson. Simon H.. Martinat. Cécile. Azzouz. Mimoun. Gillingwater. Thomas H.. 5033939. e87908.
16. Beck. David B.. Ferrada. Marcela A.. Sikora. Keith A.. Ombrello. Amanda K.. Collins. Jason C.. Pei. Wuhong. Balanda. Nicholas. Ross. Daron L.. Ospina Cardona. Daniela. Wu. Zhijie. Patel. Bhavisha. 2020-10-27. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. New England Journal of Medicine. 383. 27. en. 2628–2638. 10.1056/NEJMoa2026834. 33108101. 7847551. 0028-4793.
17. Qin Z, Cui B, Jin J, Song M, Zhou B, Guo H, Qian D, He Y, Huang L . The ubiquitin-activating enzyme E1 as a novel therapeutic target for the treatment of restenosis . Atherosclerosis . 247 . 142–53 . April 2016 . 26919560 . 10.1016/j.atherosclerosis.2016.02.016 .
18. Tsukamoto S . Search for Inhibitors of the Ubiquitin-Proteasome System from Natural Sources for Cancer Therapy . Chemical & Pharmaceutical Bulletin . 64 . 2 . 112–8 . 2016 . 26833439 . 10.1248/cpb.c15-00768 . free .
19. Yamanokuchi R, Imada K, Miyazaki M, Kato H, Watanabe T, Fujimuro M, Saeki Y, Yoshinaga S, Terasawa H, Iwasaki N, Rotinsulu H, Losung F, Mangindaan RE, Namikoshi M, de Voogd NJ, Yokosawa H, Tsukamoto S . Hyrtioreticulins A-E, indole alkaloids inhibiting the ubiquitin-activating enzyme, from the marine sponge Hyrtios reticulatus . Bioorganic & Medicinal Chemistry . 20 . 14 . 4437–42 . July 2012 . 22695182 . 10.1016/j.bmc.2012.05.044 .