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]
^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. PMID1845793.
^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. PMID18662542.
^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. PMID12646924.
^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. PMID15694336.
^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. PMID26919560.
Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (October 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–92. doi:10.1038/nbt1240. PMID16964243.
Anindya R, Aygün O, Svejstrup JQ (November 2007). "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. doi:10.1016/j.molcel.2007.10.008. PMID17996703.
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 (May 2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID16713569.
Nicassio F, Corrado N, Vissers JH, Areces LB, Bergink S, Marteijn JA, Geverts B, Houtsmuller AB, Vermeulen W, Di Fiore PP, Citterio E (November 2007). "Human USP3 is a chromatin modifier required for S phase progression and genome stability". Current Biology. 17 (22): 1972–7. doi:10.1016/j.cub.2007.10.034. PMID17980597.
Su ZL, Mo XL, Feng ZY, Lin HL, Ding YG (September 2008). "UBE1 expression in extranodal NK/T cell lymphoma, nasal type". Leukemia & Lymphoma. 49 (9): 1821–2. doi:10.1080/10428190802187171. PMID18661401.
Wang X, Shi Y, Wang J, Huang G, Jiang X (September 2008). "Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation". The Biochemical Journal. 414 (2): 221–9. doi:10.1042/BJ20080674. PMID18498243.
Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D (October 2008). "Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain". The Biochemical Journal. 415 (1): 155–63. doi:10.1042/BJ20071708. PMID18498246.
