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

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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-kB 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 (TRAF6^RING) 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/TRAF6^RING 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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All data generated or analysed during this study are included in the manuscript and supporting files.

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Priyesh Mohanty

National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India

Competing interests
The authors declare that no competing interests exist.
Rashmi Agrata

National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India

Competing interests
The authors declare that no competing interests exist.
Batul Ismail Habibullah

National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India

Competing interests
The authors declare that no competing interests exist.
Arun Geetha Surendran

National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India

Competing interests
The authors declare that no competing interests exist.
Ranabir Das

National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India

For correspondence
rana@ncbs.res.in

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5114-6817

Funding

Tata Institute of Fundamental Research (Intramural grant)

Ranabir Das

Department of Biotechnology , Ministry of Science and Technology (Ramalingaswamy Fellowship)

Ranabir Das

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.