SUMO's N-terminus Inhibits SUMO-SIM Interactions

Core Concepts

The author argues that the intrinsically disordered N-terminus of SUMO proteins acts as an intramolecular inhibitor of SUMO - SIM interactions, contributing to specificity and regulation in the SUMOylation process.

Abstract

The study reveals that the N-termini of human, C. elegans, and yeast SUMO proteins inhibit SIM binding through fast and fuzzy interactions with the core. Deletion experiments show enhanced protein interactions when the N-terminus is removed. Molecular dynamics simulations support these findings by demonstrating reversible interactions between the N-terminus and core regions. Post-translational modifications may regulate this inhibitory effect, providing a mechanism for fine-tuning SIM-dependent interactions.

Stats

Many SUMO substrates carry short motifs (SIMs) mediating low affinity interactions.
Over 600 E3 ligases are known for Ubiquitylation compared to fewer than ten for SUMOylation.
Human genome encodes five SUMO paralogues: ubiquitously expressed SUMO1 and twins SUMO2/3.
Three classes of SUMO-binding motifs identified include SIMs with hydrophobic residues.
The orientation of SIMs can be reversed in some cases.
Hydrophobic amino acids in SIMs insert as a β-strand into the hydrophobic groove formed by the β2-strand and α1-helix of SUMO.

Quotes

"The interaction mode of SUMOs’ N-termini with the SUMO core is in line with the fuzzy complex model."
"Our findings offer an intriguing explanation for the presence and strict evolutionary conservation of SUMOs’ intrinsically disordered N-termini."

Key Insights Distilled From

SUMO’s intrinsically disordered N-terminus is an intramolecular inhibitor of SUMO - SIM interactions

by Rich... at www.biorxiv.org 01-05-2024

https://www.biorxiv.org/content/10.1101/2024.01.04.574143v1

Deeper Inquiries

How do posttranslational modifications influence the inhibitory effect of SUMOs' intrinsically disordered N-termini

Posttranslational modifications can influence the inhibitory effect of SUMOs' intrinsically disordered N-termini by altering the electrostatic interactions between the N-terminus and the SIM-binding groove. For example, phosphorylation of specific residues in the N-terminus can increase its residence time on the SIM-binding groove, strengthening the inhibition of SIM-dependent interactions. In contrast, mutations that mimic phosphorylation or acetylation may disrupt these interactions, leading to a reduction in inhibitory effects. The dynamic nature of these modifications allows for fine-tuning of SUMO functions and specificity in protein-protein interactions.

What implications could this research have on understanding other protein-protein interaction mechanisms

This research sheds light on how intrinsically disordered regions (IDRs), such as SUMOs' N-termini, play crucial roles in regulating protein-protein interactions. By acting as cis-inhibitors through fuzzy complexes with structured domains like SIM-binding grooves, IDRs provide a mechanism for controlling specificity and dynamics in interaction networks. Understanding this mode of regulation could have implications beyond SUMOylation pathways, offering insights into how other proteins utilize IDRs to modulate complex signaling cascades and cellular processes.

How might targeting the interaction between IDRs and structured domains lead to novel therapeutic strategies

Targeting the interaction between intrinsically disordered regions (IDRs) and structured domains presents an exciting opportunity for developing novel therapeutic strategies. By disrupting or enhancing these transient interactions using small molecules or peptides designed to mimic posttranslational modifications or key binding motifs within IDRs, it may be possible to modulate critical protein-protein interactions involved in disease pathways. This approach could lead to innovative treatments targeting specific protein complexes without affecting global cellular processes regulated by traditional drug targets like enzymes or receptors.