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bioRxiv · 10.1101/665992

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

Mohanty, P.·Rashmi,·Habibullah, B. I.·G S, A.·Das, R.
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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-{kappa}B inflammatory response is inactivated. The precise role of deamidation in inactivating 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 where a post-translational modification perturbs the conformation and stability of transient complexes to inhibit protein-protein association.

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Mohanty, P., Rashmi,, Habibullah, B. I., G S, A., Das, R.. 2019-06-13. Deamidation disrupts native and transient contacts to weaken the interaction between UBC13 and RING-finger E3 ligases. https://doi.org/10.1101/665992

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