Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases.
The deamidase OspI from enteric bacteria Shigella flexneri deamidates a glutamine residue in the host ubiquitin-conjugating enzyme UBC13 and converts it to glutamate (Q100E). Consequently, its polyubiquitination activity in complex with the RING-finger ubiquitin ligase TRAF6 and the downstream NF-?B inflammatory response is silenced. The precise role of deamidation in ... silencing the UBC13/TRAF6 complex is unknown. We report that deamidation inhibits the interaction between UBC13 and TRAF6 RING-domain (TRAF6RING) by perturbing both the native and transient interactions. Deamidation creates a new intramolecular salt-bridge in UBC13 that competes with a critical intermolecular salt-bridge at the native UBC13/TRAF6RING interface. Moreover, the salt-bridge competition prevents transient interactions necessary to form a typical UBC13/RING complex. Repulsion between E100 and the negatively charged surface of RING also prevents transient interactions in the UBC13/RING complex. Our findings highlight a mechanism wherein a post-translational modification perturbs the conformation and stability of transient complexes to inhibit protein-protein association.
Mesh Terms:
Amidohydrolases, Amino Acid Motifs, Bacterial Proteins, Binding Sites, Cloning, Molecular, Crystallography, X-Ray, Escherichia coli, Gene Expression, Glutamic Acid, Glutamine, Host-Pathogen Interactions, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Processing, Post-Translational, Recombinant Proteins, Shigella flexneri, Substrate Specificity, Ubiquitin-Conjugating Enzymes, Ubiquitination
Amidohydrolases, Amino Acid Motifs, Bacterial Proteins, Binding Sites, Cloning, Molecular, Crystallography, X-Ray, Escherichia coli, Gene Expression, Glutamic Acid, Glutamine, Host-Pathogen Interactions, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Processing, Post-Translational, Recombinant Proteins, Shigella flexneri, Substrate Specificity, Ubiquitin-Conjugating Enzymes, Ubiquitination
Elife
Date: Dec. 22, 2018
PubMed ID: 31638574
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