Abstract
Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein’s function by recruiting other cellular proteins. Recruitment frequently involves a non-covalent interaction between SUMO and a SUMO-interacting motif (SIM) in the interacting protein. SIMs generally consist of a four-residue-long hydrophobic stretch of amino acids with aliphatic non-polar side chains flanked on one side by negatively charged amino acid residues. The SIM assumes an extended β-strand-like conformation and binds to a conserved hydrophobic groove in SUMO. In addition to hydrophobic interactions between the SIM non-polar core and hydrophobic residues in the groove, the negatively charged residues in the SIM make favorable electrostatic contacts with positively charged residues in and around the groove. The SIM/SUMO interaction can be regulated by the phosphorylation of residues adjacent to the SIM hydrophobic core, which provide additional negative charges for favorable electrostatic interaction with SUMO. The SUMO interactome consists of hundreds or perhaps thousands of SIM-containing proteins, but we do not fully understand how each SUMOylated protein selects the set of SIM-containing proteins appropriate to its function. SIM/SUMO interactions have critical functions in a large number of essential cellular processes including the formation of membraneless organelles by liquid–liquid phase separation, epigenetic regulation of transcription through histone modification, DNA repair, and a variety of host–pathogen interactions.
Highlights
Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-like protein family and, like ubiquitin, SUMO can be covalently attached to lysine side chains in a variety of target proteins
A second, and perhaps even more remarkable example of how SUMO-interacting motif (SIM)/SUMO interactions in promyelocytic leukemia (PML)-NBs bring about a complex biological response, involves ICP0, a SUMO-targeted ubiquitin ligases (STUbLs) encoded in the Herpes Simplex Virus 1 (HSV-1) genome
SUMOylation is like any reversible post-translational protein modification, in which a covalent change to protein structure serves as an on–off switch that alters protein function
Summary
Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-like protein family and, like ubiquitin, SUMO can be covalently attached to lysine side chains in a variety of target proteins. While we do not yet understand all the factors that influence binding orientation, it seems clear that electrostatic interactions involving the negatively charged residues play important roles in determining both affinity and orientation of the SUMO/SIM complex. Phosphorylation of serine residues adjacent to the SIM hydrophobic core has been shown to stimulate binding to SUMO by introducing negative charges into the SIM that engage in favorable electrostatic interactions with positive charges in SUMO. The structure of the complex between SUMO-1 and the Daxx SIM as determined by X-ray crystallography supports the importance of these electrostatic interactions (Figure 1C) This structure shows that a number of positively charged residues in SUMO-1 (K37, K39, H43, and K46) provide a favorable electrostatic environment for the negative charges introduced as a result of phosphorylation of the Daxx SIM [17]. This demonstrates that the plasticity of the SUMO/SIM interface may lead to SIM-specific effects of SUMO acetylation on SIM binding
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