Journal
MOLECULAR CELL
Volume 74, Issue 5, Pages 922-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.03.028
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Funding
- National Key Research and Development Programs of China [2018YFA0508000, 2017YFA0504000, 2017YFA0505900, 2016YFA0501500]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB29020202, XDB08020202]
- program Youth Innovation Promotion Association CAS [2017127]
- National Natural Science Foundation of China (NSFC) [31470245]
- Natural Science Foundation of Hubei Province of China [2015CFA030, 2017CFB379]
- Foundation for Innovative Research Team of Hubei Provincial Department of Education [T201713]
- Fundamental Research Funds for the Central Universities [2662017PY011, 2662018PY028]
- Huazhong Agricultural University Scientific & Technological Self-Innovation Foundation [2017RC003]
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Enteropathogenic E. coli NleB and related type III effectors catalyze arginine GlcNAcylation of death domain (DD) proteins to block host defense, but the underlying mechanism is unknown. Here we solve crystal structures of NleB alone and in complex with FADD-DD, UDP, and Mn2+ as well as NleB-GlcNAcylated DDs of TRADD and RIPK1. NleB adopts a GT-A fold with a unique helix-pair insertion to hold FADD-DD; the interface contacts explain the selectivity of NleB for certain DDs. The acceptor arginine is fixed into a cleft, in which Glu253 serves as a base to activate the guanidinium. Analyses of the enzyme-substrate complex and the product structures reveal an inverting sugar-transfer reaction and a detailed catalytic mechanism. These structural insights are validated by mutagenesis analyses of NleB-mediated GlcNAcylation in vitro and its function in mouse infection. Our study builds a structural framework for understanding of NleB-catalyzed arginine GlcNAcylation of host death domain.
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