UBA1 Gene

UBA1 (UBA1 is the acronym for "Ubiquitin Like Modifier Activating Enzyme 1") is a protein-coding gene located on chromosome Xp11.3 ( Lee I et al. 2008). The gene is part of a gene cluster on chromosome Xp11.23. Alternatively spliced transcript variants encoding the same protein have been described. An important paralog of this gene is UBA7.

The enzyme encoded by the UBA1 gene (E1) is a 110-120 kDa monomeric protein. E1 consists of 4 building blocks:

1. Adenylation domain consisting of two MoeB/ThiF homology motifs, the latter of which binds ATP and Ub.
2. catalytic cysteine half-domains containing the E1 activity center cysteine inserted into each of the adenylation domains
3. Four-helix bundle representing a second insertion in the inactive adenylation domain immediately following the first catalytic cysteine half-domain
4. C-terminal ubiquitin fold domain that recruits specific E2.

UBA1 catalyzes the first step of ubiquitin conjugation also called ubiquitination to mark cellular proteins for degradation. Specifically, UBA1 catalyzes the ATP-dependent adenylation of ubiquitin, forming a thioester bond between the two. It also participates in subsequent steps of ubiquitination as a Ub carrier. In humans, there are only two ubiquitin-activating enzymes, UBA1 (E1) and UBA6, and thus UBA1 is largely responsible for protein ubiquitination in humans (Moudry P et al (2012). Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation. In addition, UBA1 contributes to the regulation of the NEDD8 pathway and is thus involved in protein folding and in the attenuation of ubiquitin degradation upon stress.

Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2.

UBA1 has also been linked to other neurodegenerative diseases, including spinal muscular atrophy, as well as cancer and tumors.

An autoinflammatory disorder identified in 2020 and termed VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to a mutation (of methionine41) in UBA1 (Arlet JB et al. 2021; Ross C et al. 2021).

1. Arlet JB et al (2021) Mutant UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 384: 2163.
2. Beck DB et al (2020) Somatic mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 383:2628-2638.
3. Grayson PC et al (2021) VEXAS syndrome. Blood 137:3591-3594.
4. Lee I et al (2008) Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes. Cell 134: 268-278.
5. Moudry P et al (2012) Ubiquitin-activating enzyme UBA1 is required for cellular response to DNA damage. Cell Cycle 11: 1573-1582.
6. Ross C et al (2021) Somatic mutation in UBA1 and ANCA-associated vasculitis. J Rheumatol. 48:1626-1627