Structural basis for arginine glycosylation of host substrates by bacterial effector proteins

Jun Bae Park, Young Hun Kim, Youngki Yoo, Juyeon Kim, Sung-Hoon Jun, Jin Won Cho, Samir El Qaidi, Samuel Walpole, Serena Monaco, Ana A. García-García, Miaomiao Wu, Michael P. Hays, Ramon Hurtado-Guerrero (), Jesus Angulo (), Philip R. Hardwidge, Jeon-Soo Shin () and Hyun-Soo Cho ()
Additional contact information
Jun Bae Park: Yonsei University, 50 Yonsei-ro, Seodaemun-gu
Young Hun Kim: Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu
Youngki Yoo: Yonsei University, 50 Yonsei-ro, Seodaemun-gu
Juyeon Kim: Yonsei University, 50 Yonsei-ro, Seodaemun-gu
Sung-Hoon Jun: Yonsei University, 50 Yonsei-ro, Seodaemun-gu
Jin Won Cho: Yonsei University, 50 Yonsei-ro, Seodaemun-gu
Samir El Qaidi: Kansas State University
Samuel Walpole: University of East Anglia, Norwich Research Park
Serena Monaco: University of East Anglia, Norwich Research Park
Ana A. García-García: BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D
Miaomiao Wu: Kansas State University
Michael P. Hays: Kansas State University
Ramon Hurtado-Guerrero: BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D
Jesus Angulo: University of East Anglia, Norwich Research Park
Philip R. Hardwidge: Kansas State University
Jeon-Soo Shin: Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu
Hyun-Soo Cho: Yonsei University, 50 Yonsei-ro, Seodaemun-gu

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract The bacterial effector proteins SseK and NleB glycosylate host proteins on arginine residues, leading to reduced NF-κB-dependent responses to infection. Salmonella SseK1 and SseK2 are E. coli NleB1 orthologs that behave as NleB1-like GTs, although they differ in protein substrate specificity. Here we report that these enzymes are retaining glycosyltransferases composed of a helix-loop-helix (HLH) domain, a lid domain, and a catalytic domain. A conserved HEN motif (His-Glu-Asn) in the active site is important for enzyme catalysis and bacterial virulence. We observe differences between SseK1 and SseK2 in interactions with substrates and identify substrate residues that are critical for enzyme recognition. Long Molecular Dynamics simulations suggest that the HLH domain determines substrate specificity and the lid-domain regulates the opening of the active site. Overall, our data suggest a front-face SNi mechanism, explain differences in activities among these effectors, and have implications for future drug development against enteric pathogens.

Date: 2018
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DOI: 10.1038/s41467-018-06680-6

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