Molecular mechanisms in SUMO conjugation

Abstract

The small ubiquitin-like modifier (SUMO) is a post-translational modifier that can regulate the function of hundreds of proteins inside the cell. SUMO belongs to the ubiquitin-like family of proteins that can be attached to target proteins by a dedicated enzymatic cascade pathway formed by E1, E2 and E3 enzymes. SUMOylation is involved in many cellular pathways, having in most instances essential roles for their correct function. In this review, we want to highlight the latest research on the molecular mechanisms that lead to the formation of the isopeptidic bond between the lysine substrate and the C-terminus of SUMO. In particular, we will focus on the recent discoveries on the catalytic function of the SUMO E3 ligases revealed by structural and biochemical approaches. Also, we will discuss important questions regarding specificity in SUMO conjugation, which it still remains as a major issue due to the small number of SUMO E3 ligases discovered so far, in contrast with the large number of SUMO conjugated proteins in the cell.

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

“…Eukaryotes express at least one member of the SUMO family. SUMOylation, similar to ubiquitination, is essential to many cellular processes, including transcriptional control, DNA repair, and regulation of protein-protein interactions, subcellular localization, and proteolytic processes [100][101][102]. In humans, the SUMO family members include SUMO1, SUMO2, and SUMO3.…”

Phase Separation Can Increase Enzyme Activity by Concentration and Molecular Organization

“…We generated a model condensate based on inducible targeting of the SUMOylation enzymatic cascade ( Figure 1A) 43 into phase separated droplets composed of a polySH3 domain protein (polySH3 3 , with three tandem SH3 domains) and its polyproline-rich-motif (polyPRM 5 , with five tandem PRMs) ligand ( Figure 1B) 13 . The cascade attaches the 12 kDa Small Ubiquitin-like Modifier protein, SUMO, to diverse substrates.…”

SUMOylation- and GAR1-dependent regulation of dyskerin nuclear and subnuclear localization

“…Consistent with the hypothesis that SUMO removal may regulate nucleolar localization of SUMO-target proteins, depletion of SENP3, and thus reduction of nucleolar deSUMOylation, has been reported to lead to nucleolar release of the PELP1-TEX10-WDR18 complex (68) Here we also report that the efficient interaction between dyskerin and GAR1 is mediated through a newly characterized SIM in GAR1 (amino acids 70-VVLLG-74). SIMs are typically short hydrophobic stretches of residues that can form an extended β-strand backbone, which then non-covalently interacts with SUMO moieties to foster stronger or more frequent SUMOmediated protein-protein interactions (38). It is important to note that this predicted motif is not well conserved in lower eukaryotes or archaea (58).…”

“…The posttranslational modification SUMOylation has been demonstrated to affect nuclear and subnuclear localization of a number of protein targets, including resident proteins of the nucleolus (35)(36)(37). This modification involves conjugation of small ubiquitin-like modifier (SUMO) protein to lysine residues of target proteins in an E1 activating (SAE1/SAE2) and E2 conjugating (Ubc9) enzyme-dependent manner, often with the help of one of many E3 SUMO ligases, and promoted by a SUMOylation consensus motif in target proteins (ψKXE/D -where ψ is a hydrophobic residue and X is any residue) (38). While SUMOylation has been reported to regulate various functions of target proteins, a key aspect of SUMOylation is mediating proteinprotein interactions between SUMO targets and proteins containing SUMO-interacting motifs (SIMs) which non-covalently bind SUMO (39)(40)(41).…”