Small Ubiquitin-like Modifier 2 (SUMO2), also known as Sentrin2 and SMT3B is synthesized as a 95 amino acid (aa), propeptide with a predicted 11 kDa. SUMO2 contains a two aa C-terminal prosegment and an 18 aa N-terminal protein interacting region between aa 33-50. Human SUMO2 shares 100% aa sequence identity with mouse SUMO2. SUMO2 also has very high aa sequence identity with SUMO3 and SUMO4, 86% and 85%, respectively. SUMO2 shares only 44% aa sequence identity with SUMO1. SUMOs are a family of small, related proteins that can be enzymatically attached to a target protein by a post-translational modification process termed SUMOylation. All SUMO proteins share a conserved ubiquitin domain and a C-terminal diglycine cleavage/attachment site. Following prosegment cleavage, the C-terminal glycine residue of SUMO2 is enzymatically attached to a lysine residue on a target protein. In humans, SUMO2 is conjugated to a variety of molecules in the presence of the SAE1/UBA2 SUMO-activating (E1) enzyme and the UBE2I/Ubc9 SUMO-conjugating (E2) enzyme. In yeast, the SUMO-activating (E1) enzyme is Aos1/Uba2p. Because of the high level of aa sequence identity most studies report effects of SUMO2/3. For example, post-translational addition of SUMO2/3 was shown to modulate the function of ARHGAP21, a RhoGAP protein known to be involved in cell migration. Other reports indicate that the SUMOylation with SUMO2/3, but not SUMO1, may represent an important mechanism to protect neurons during episodes of cerebral ischemia. However, studies suggest that SUMO2/3 expression is regulated in an isoform-specific manner since oxidative stress downregulated the transcription of SUMO3 but not SUMO2. All SUMO isoforms are translated with additional C-terminal residues that have to be removed to generate the active protein. Pro-SUMO-2 (95 aa) is the inactive precursor of SUMO-2 (93 aa) and is processed at the C-terminus by SUMO-2 specific proteases (SENPs). The resulting SUMO-2 protein has the conserved C-terminal Gly-Gly residues that function in activation and conjugation reactions.