UBA1

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene.[5][6] UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes.[5][7] This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.[8][9]

UBA1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesUBA1, A1S9, A1S9T, A1ST, AMCX1, CFAP124, GXP1, POC20, SMAX2, UBA1A, UBE1, UBE1X, ubiquitin like modifier activating enzyme 1, VEXAS
External IDsOMIM: 314370 MGI: 98890 HomoloGene: 22002 GeneCards: UBA1
Orthologs
SpeciesHumanMouse
Entrez

7317

22201

Ensembl

ENSG00000130985

ENSMUSG00000001924

UniProt

P22314
Q5JRS2

Q02053

RefSeq (mRNA)

NM_003334
NM_153280

NM_001136085
NM_001276316
NM_001276317
NM_009457

RefSeq (protein)

NP_003325
NP_695012

NP_001129557
NP_001263245
NP_001263246
NP_033483

Location (UCSC)Chr X: 47.19 – 47.22 MbChr X: 20.52 – 20.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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,[10] 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.[11] 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;[12][13][14] second, the catalytic cysteine half-domains, which contain the E1 active site cysteine inserted into each of the adenylation domains;[15] 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.[13][16][17]

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.[8][9][18] There are only two human ubiquitin-activating enzymes, UBA1 and UBA6, and thus UBA1 is largely responsible for protein ubiquitination in humans.[8][9][18] Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation.[8][9] Additionally, UBA1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during stress.[7]

Clinical significance

Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2.[5] UBA1 has also been implicated in other neurodegenerative diseases, including spinal muscular atrophy,[19] 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[8][9] Moreover, the UBA1 inhibitors 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.[9]

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.[20]

Interactions

UBA1 has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000130985 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000001924 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: ubiquitin-like modifier activating enzyme 1".
  6. Kudo M, Sugasawa K, Hori T, Enomoto T, Hanaoka F, Ui M (January 1991). "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. doi:10.1016/0014-4827(91)90164-P. PMID 1845793.
  7. Leidecker O, Matic I, Mahata B, Pion E, Xirodimas DP (March 2012). "The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions". Cell Cycle. 11 (6): 1142–50. doi:10.4161/cc.11.6.19559. PMID 22370482.
  8. Correale S, de Paola I, Morgillo CM, Federico A, Zaccaro L, Pallante P, Galeone A, Fusco A, Pedone E, Luque FJ, Catalanotti B (2014). "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. Bibcode:2014PLoSO...9k2082C. doi:10.1371/journal.pone.0112082. PMC 4223017. PMID 25375166.
  9. Ungermannova D, Parker SJ, Nasveschuk CG, Wang W, Quade B, Zhang G, Kuchta RD, Phillips AJ, Liu X (2012). "Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1)". PLOS ONE. 7 (1): e29208. Bibcode:2012PLoSO...729208U. doi:10.1371/journal.pone.0029208. PMC 3261141. PMID 22279528.
  10. Johnson ES, Schwienhorst I, Dohmen RJ, Blobel G (September 1997). "The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer". The EMBO Journal. 16 (18): 5509–19. doi:10.1093/emboj/16.18.5509. PMC 1170183. PMID 9312010.
  11. Lee I, Schindelin H (July 2008). "Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes". Cell. 134 (2): 268–78. doi:10.1016/j.cell.2008.05.046. PMID 18662542.
  12. Lake MW, Wuebbens MM, Rajagopalan KV, Schindelin H (November 2001). "Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex" (PDF). Nature. 414 (6861): 325–9. Bibcode:2001Natur.414..325L. doi:10.1038/35104586. PMID 11713534. S2CID 3224437.
  13. Lois LM, Lima CD (February 2005). "Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1". The EMBO Journal. 24 (3): 439–51. doi:10.1038/sj.emboj.7600552. PMC 548657. PMID 15660128.
  14. Walden H, Podgorski MS, Schulman BA (March 2003). "Insights into the ubiquitin transfer cascade from the structure of the activating enzyme for NEDD8". Nature. 422 (6929): 330–4. Bibcode:2003Natur.422..330W. doi:10.1038/nature01456. PMID 12646924. S2CID 4370095.
  15. Szczepanowski RH, Filipek R, Bochtler M (June 2005). "Crystal structure of a fragment of mouse ubiquitin-activating enzyme". The Journal of Biological Chemistry. 280 (23): 22006–11. doi:10.1074/jbc.M502583200. PMID 15774460.
  16. Huang DT, Paydar A, Zhuang M, Waddell MB, Holton JM, Schulman BA (February 2005). "Structural basis for recruitment of Ubc12 by an E2 binding domain in NEDD8's E1". Molecular Cell. 17 (3): 341–50. doi:10.1016/j.molcel.2004.12.020. PMID 15694336.
  17. Huang DT, Hunt HW, Zhuang M, Ohi MD, Holton JM, Schulman BA (January 2007). "Basis for a ubiquitin-like protein thioester switch toggling E1-E2 affinity". Nature. 445 (7126): 394–8. Bibcode:2007Natur.445..394H. doi:10.1038/nature05490. PMC 2821831. PMID 17220875.
  18. Moudry P, Lukas C, Macurek L, Hanzlikova H, Hodny Z, Lukas J, Bartek J (April 2012). "Ubiquitin-activating enzyme UBA1 is required for cellular response to DNA damage". Cell Cycle. 11 (8): 1573–82. doi:10.4161/cc.19978. PMID 22456334.
  19. 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. (2016). "Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy" (PDF). JCI Insight. 1 (11): e87908. doi:10.1172/jci.insight.87908. PMC 5033939. PMID 27699224.
  20. 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): 2628–2638. doi:10.1056/NEJMoa2026834. ISSN 0028-4793. PMC 7847551. PMID 33108101.
  21. Qin Z, Cui B, Jin J, Song M, Zhou B, Guo H, Qian D, He Y, Huang L (April 2016). "The ubiquitin-activating enzyme E1 as a novel therapeutic target for the treatment of restenosis". Atherosclerosis. 247: 142–53. doi:10.1016/j.atherosclerosis.2016.02.016. PMID 26919560.
  22. Tsukamoto S (2016). "Search for Inhibitors of the Ubiquitin-Proteasome System from Natural Sources for Cancer Therapy". Chemical & Pharmaceutical Bulletin. 64 (2): 112–8. doi:10.1248/cpb.c15-00768. PMID 26833439.
  23. 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 (July 2012). "Hyrtioreticulins A-E, indole alkaloids inhibiting the ubiquitin-activating enzyme, from the marine sponge Hyrtios reticulatus". Bioorganic & Medicinal Chemistry. 20 (14): 4437–42. doi:10.1016/j.bmc.2012.05.044. PMID 22695182.

Further reading

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