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]
^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.
^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.
S2CID14294292.
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.
S2CID5481217.
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.