| Structural highlights
Function
SSEK1_SALTY Protein-arginine N-acetylglucosaminyltransferase effector that disrupts TNF signaling in infected cells, including NF-kappa-B signaling, apoptosis and necroptosis (PubMed:23955153, PubMed:28069818, PubMed:28522607). Acts by catalyzing the transfer of a single N-acetylglucosamine (GlcNAc) to a conserved arginine residue in the death domain of host proteins TRADD and, to a lower extent, FADD: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions and assembly of the oligomeric TNF-alpha receptor complex, thereby disrupting TNF signaling (PubMed:23955153, PubMed:28069818). Also acts on host proteins without a death domain: catalyzes arginine GlcNAcylation of host GAPDH protein, thereby preventing GAPDH interaction with TRAF2, leading to inhibit NF-kappa-B signaling (PubMed:28522607). Catalyzes GlcNAcylation of host tubulin-folding cofactor TBCB, thereby promoting microtubule stability (PubMed:32366039). Also mediates auto-GlcNAcylation, which is required for activity toward death domain-containing host target proteins (PubMed:32366039).[1] [2] [3] [4]
Publication Abstract from PubMed
The bacterial effector proteins SseK and NleB glycosylate host proteins on arginine residues, leading to reduced NF-kappaB-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.
Structural basis for arginine glycosylation of host substrates by bacterial effector proteins.,Park JB, Kim YH, Yoo Y, Kim J, Jun SH, Cho JW, El Qaidi S, Walpole S, Monaco S, Garcia-Garcia AA, Wu M, Hays MP, Hurtado-Guerrero R, Angulo J, Hardwidge PR, Shin JS, Cho HS Nat Commun. 2018 Oct 16;9(1):4283. doi: 10.1038/s41467-018-06680-6. PMID:30327479[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Li S, Zhang L, Yao Q, Li L, Dong N, Rong J, Gao W, Ding X, Sun L, Chen X, Chen S, Shao F. Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature. 2013 Sep 12;501(7466):242-6. PMID:23955153 doi:10.1038/nature12436
- ↑ Günster RA, Matthews SA, Holden DW, Thurston TLM. SseK1 and SseK3 Type III Secretion System Effectors Inhibit NF-κB Signaling and Necroptotic Cell Death in Salmonella-Infected Macrophages. Infect Immun. 2017 Feb 23;85(3):e00010-17. PMID:28069818 doi:10.1128/IAI.00010-17
- ↑ El Qaidi S, Chen K, Halim A, Siukstaite L, Rueter C, Hurtado-Guerrero R, Clausen H, Hardwidge PR. NleB/SseK effectors from Citrobacter rodentium, Escherichia coli, and Salmonella enterica display distinct differences in host substrate specificity. J Biol Chem. 2017 Jul 7;292(27):11423-11430. PMID:28522607 doi:10.1074/jbc.M117.790675
- ↑ Araujo-Garrido JL, Baisón-Olmo F, Bernal-Bayard J, Romero F, Ramos-Morales F. Tubulin Folding Cofactor TBCB is a Target of the Salmonella Effector Protein SseK1. Int J Mol Sci. 2020 Apr 30;21(9):3193. PMID:32366039 doi:10.3390/ijms21093193
- ↑ Park JB, Kim YH, Yoo Y, Kim J, Jun SH, Cho JW, El Qaidi S, Walpole S, Monaco S, Garcia-Garcia AA, Wu M, Hays MP, Hurtado-Guerrero R, Angulo J, Hardwidge PR, Shin JS, Cho HS. Structural basis for arginine glycosylation of host substrates by bacterial effector proteins. Nat Commun. 2018 Oct 16;9(1):4283. doi: 10.1038/s41467-018-06680-6. PMID:30327479 doi:http://dx.doi.org/10.1038/s41467-018-06680-6
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