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Elife. 2019 Oct 22;8. pii: e49223. doi: 10.7554/eLife.49223.

Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases.

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1
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India.

Abstract

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-κB 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.

KEYWORDS:

E. coli; MD simulations; NMR spectroscopy; Shigella; biochemistry; chemical biology; deamidation; transient complex; ubiquitination

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