UBA1

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UBA1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases UBA1, A1S9, A1S9T, A1ST, AMCX1, CFAP124, GXP1, POC20, SMAX2, UBA1A, UBE1, UBE1X, ubiquitin like modifier activating enzyme 1
External IDs OMIM: 314370 MGI: 98890 HomoloGene: 22002 GeneCards: 7317
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_003334
NM_153280

NM_001136085
NM_001276316
NM_001276317
NM_009457

RefSeq (protein)

NP_003325.2
NP_695012.1

NP_001129557.1
NP_001263245.1
NP_001263246.1
NP_033483.2

Location (UCSC) Chr X: 47.19 – 47.22 Mb Chr X: 20.66 – 20.68 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene.[3][4] UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes.[3][5] This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.[6][7]

Structure[edit]

Gene[edit]

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

Protein[edit]

The UBA1 for ubiquitin(Ub) is a 110–120 kDa monomeric protein, and the UBA1 for the ubiquitin-like proteins(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,[8] 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.[9] 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;[10][11][12] second, the catalytic cysteine half-domains, which contain the E1 active site cysteine inserted into each of the adenylation domains;[13] 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.[11][14][15]

Function[edit]

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.[6][7][16] There are only two human ubiquitin-activating enzymes, UBA1 and UBA6, and thus UBA1 is largely responsible for protein ubiquitination in humans.[6][7][16] Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation.[6][7] Additionally, UBA1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during stress.[5]

Clinical significance[edit]

Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2.[3] UBA1 has also been implicated in neurodegenerative diseases, cancer, and tumor. Because 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[6][7] 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.[7]

Interactions[edit]

UBA1 has been shown to interact with:

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b c "Entrez Gene: ubiquitin-like modifier activating enzyme 1". 
  4. ^ 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. 
  5. ^ a b 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. 
  6. ^ a b c d e f 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. doi:10.1371/journal.pone.0112082. PMID 25375166. 
  7. ^ a b c d e f 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. doi:10.1371/journal.pone.0029208. PMID 22279528. 
  8. ^ 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 1170183free to read. PMID 9312010. 
  9. ^ 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. 
  10. ^ Lake MW, Wuebbens MM, Rajagopalan KV, Schindelin H (November 2001). "Mechanism of ubiquitin activation revealed by the structure of a bacterial MoeB-MoaD complex". Nature. 414 (6861): 325–9. doi:10.1038/35104586. PMID 11713534. 
  11. ^ a b 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 548657free to read. PMID 15660128. 
  12. ^ 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. doi:10.1038/nature01456. PMID 12646924. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. doi:10.1038/nature05490. PMC 2821831free to read. PMID 17220875. 
  16. ^ a b 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. 
  17. ^ 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. 
  18. ^ 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. 
  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 (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[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.