Ubiquitin-Like Modifier Activating Enzyme 3 (UBA3) is a crucial component in the ubiquitin-proteasome system, which is responsible for the degradation of proteins within the cell. This enzyme is part of the E1 ubiquitin-activating enzyme family and plays a significant role in the neddylation pathway, which is essential for various cellular processes, including cell division, signaling, and embryogenesis .
UBA3 is encoded by the UBA3 gene located on chromosome 3p14.1 . The gene produces a protein that consists of 442 amino acids and shares 43% sequence identity with its yeast homolog . The UBA3 protein forms a heterodimer with APPBP1 (amyloid beta precursor protein binding protein 1), which is necessary for its function .
UBA3, in conjunction with APPBP1, forms the NEDD8-activating enzyme (NAE). This enzyme complex is responsible for the activation of NEDD8, a ubiquitin-like protein. The activation process involves the adenylation of the C-terminal glycine residue of NEDD8 with ATP, followed by the formation of a thioester bond between NEDD8 and the catalytic cysteine residue of UBA3 . This activated NEDD8 is then transferred to specific target proteins, regulating their stability and function.
The neddylation pathway, mediated by UBA3, is crucial for the regulation of the cullin-RING ubiquitin ligases (CRLs). These ligases are involved in the ubiquitination and subsequent degradation of various proteins, thereby controlling numerous cellular processes . Dysregulation of this pathway can lead to various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions.
Research on UBA3 has provided insights into its role in cellular homeostasis and disease. The recombinant form of UBA3 is used in various studies to understand its function and to develop potential therapeutic interventions. For instance, inhibitors targeting the NEDD8-activating enzyme are being explored as potential treatments for cancer, as they can disrupt the degradation of proteins that promote tumor growth .