Uba2SAE2

Uba2SAE2 refers to the SUMO-activating enzyme subunit 2, commonly known as SAE2, encoded by the UBA2 gene in humans. It is the large subunit of the heterodimeric SUMO-activating enzyme (SAE1/SAE2) that catalyzes the first, rate-limiting step of SUMO (Small Ubiquitin-like Modifier) conjugation.

Function and mechanism: SAE2 forms an ATP-dependent thioester bond with SUMO at its active-site cysteine and, together with SAE1 (Aos1), activates SUMO for transfer. The activated SUMO is then transferred first to the E2 enzyme UBC9 and subsequently to target lysines on substrate proteins, often with the assistance of SUMO ligases (E3s). This cascade places SAE2 at a central position in the SUMOylation pathway, regulating numerous substrates involved in diverse cellular processes.

Structure and interactions: SAE2 contains domains that coordinate SUMO activation and thioester formation and functions in concert with SAE1 to form the functional E1 enzyme. It physically interacts with SAE1, UBC9, and a range of SUMOylation substrates and cofactors, enabling substrate specificity and pathway modulation. Localization is primarily nuclear, with shuttling to the cytoplasm reported for some contexts, reflecting the broad range of SUMO targets.

Biological significance: SUMOylation influences protein stability, localization, and activity, contributing to DNA repair, transcriptional regulation, chromatin dynamics, and cell cycle control. As a core component of the SUMOylation machinery, SAE2 is essential for proper SUMO conjugation in many organisms.

Clinical relevance: Alterations in SUMO pathway components, including SAE2/UBA2, have been linked to cancer and neurodegenerative diseases in various studies, highlighting the pathway’s importance for cellular homeostasis.

See also: SUMOylation, SAE1, UBC9, Aos1.