UBA1

Last updated
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, VEXAS
External IDs OMIM: 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 Mb Chr X: 20.52 – 20.55 Mb
PubMed search [3] [4]
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. [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]

Contents

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 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. [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:

Related Research Articles

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Deubiquitinating enzyme</span>

Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin from proteins. Ubiquitin is attached to proteins in order to regulate the degradation of proteins via the proteasome and lysosome; coordinate the cellular localisation of proteins; activate and inactivate proteins; and modulate protein-protein interactions. DUBs can reverse these effects by cleaving the peptide or isopeptide bond between ubiquitin and its substrate protein. In humans there are nearly 100 DUB genes, which can be classified into two main classes: cysteine proteases and metalloproteases. The cysteine proteases comprise ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs) and ovarian tumour proteases (OTU). The metalloprotease group contains only the Jab1/Mov34/Mpr1 Pad1 N-terminal+ (MPN+) (JAMM) domain proteases.

<span class="mw-page-title-main">Ubiquitin-activating enzyme</span> Class of enzymes

Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction, which can target a protein for degradation via a proteasome. This covalent bond of ubiquitin or ubiquitin-like proteins to targeted proteins is a major mechanism for regulating protein function in eukaryotic organisms. Many processes such as cell division, immune responses and embryonic development are also regulated by post-translational modification by ubiquitin and ubiquitin-like proteins.

Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ubiquitin-carrier enzymes, perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.

<span class="mw-page-title-main">NEDD4</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.

<span class="mw-page-title-main">NEDD8</span>

NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.

<span class="mw-page-title-main">NEDD4L</span> Protein-coding gene in the species Homo sapiens

Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 is an enzyme of the NEDD4 family. In human the protein is encoded by the NEDD4L gene. In mouse the protein is commonly known as NEDD4-2 and the gene Nedd4-2.

<span class="mw-page-title-main">UBE2L3</span> Protein-coding gene in humans

Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene. As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation. The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease (CD), and systemic lupus erythematosus.

<span class="mw-page-title-main">CDC34</span> Protein-coding gene in the species Homo sapiens

CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.

<span class="mw-page-title-main">Ubiquitin D</span> Protein-coding gene in the species Homo sapiens

Ubiquitin D is a protein that in humans is encoded by the UBD gene, also known as FAT10. UBD acts like ubiquitin, by covalently modifying proteins and tagging them for destruction in the proteasome.

<span class="mw-page-title-main">UBE2D3</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene.

<span class="mw-page-title-main">APPBP1</span> Protein-coding gene in the species Homo sapiens

NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.

<span class="mw-page-title-main">UBE1C</span> Protein-coding gene in the species Homo sapiens

NEDD8-activating enzyme E1 catalytic subunit is a protein that in humans is encoded by the UBA3 gene.

<span class="mw-page-title-main">UBE2E1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 E1 is a protein that in humans is encoded by the UBE2E1 gene.

<span class="mw-page-title-main">UBE2M</span> Protein-coding gene in the species Homo sapiens

NEDD8-conjugating enzyme Ubc12 is a protein that in humans is encoded by the UBE2M gene.

<span class="mw-page-title-main">ATG7</span> Protein-coding gene in the species Homo sapiens

Autophagy related 7 is a protein in humans encoded by ATG7 gene. Related to GSA7; APG7L; APG7-LIKE.

<span class="mw-page-title-main">UBA2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-like 1-activating enzyme E1B (UBLE1B) also known as SUMO-activating enzyme subunit 2 (SAE2) is an enzyme that in humans is encoded by the UBA2 gene.

<span class="mw-page-title-main">UBE2Z</span> Protein-coding gene in the species Homo sapiens

Ubiquitin conjugating enzyme E2 Z (UBE2Z), also known as UBA6-specific E2 enzyme 1 (USE1), is an enzyme that in humans is encoded by the UBE2Z gene on chromosome 17. It is ubiquitously expressed in many tissues and cell types. UBE2Z is an E2 ubiquitin conjugating enzyme and participates in the second step of protein ubiquitination during proteolysis. A genome-wide association study (GWAS) revealed the UBE2Z gene to be associated with chronic kidney disease. The UBE2Z gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Ubiquitin-like protein</span> Family of small proteins

Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class to be discovered, ubiquitin (Ub), best known for its role in regulating protein degradation through covalent modification of other proteins. Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry. UBLs are involved in a widely varying array of cellular functions including autophagy, protein trafficking, inflammation and immune responses, transcription, DNA repair, RNA splicing, and cellular differentiation.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000130985 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 "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. 1 2 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. 1 2 3 4 5 6 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. 1 2 3 4 5 6 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. 1 2 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. 1 2 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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