View source for 6ggr


==Crystal structure of Salmonella zinc metalloprotease effector GtgA in complex with p65==
<StructureSection load='6ggr' size='340' side='right' caption='[[6ggr]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ggr]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice] and [http://en.wikipedia.org/wiki/Salt1 Salt1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GGR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GGR FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rela, Nfkb3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), gtgA, STM14_1166 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=588858 SALT1])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ggr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ggr OCA], [http://pdbe.org/6ggr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ggr RCSB], [http://www.ebi.ac.uk/pdbsum/6ggr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ggr ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/TF65_MOUSE TF65_MOUSE]] NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression (By similarity). The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.<ref>PMID:21131967</ref> <ref>PMID:22244329</ref>  
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== Publication Abstract from PubMed ==
The closely related type III secretion system zinc metalloprotease effector proteins GtgA, GogA, and PipA are translocated into host cells during Salmonella infection. They then cleave nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) transcription factor subunits, dampening activation of the NF-kappaB signaling pathway and thereby suppressing host immune responses. We demonstrate here that GtgA, GogA, and PipA cleave a subset of NF-kappaB subunits including p65, RelB, and cRel but not NF-kappaB1 and NF-kappaB2, whereas the functionally similar type III secretion system effector NleC of enteropathogenic and enterohemorrhagic Escherichiacoli cleaved all five NF-kappaB subunits. Mutational analysis of NF-kappaB subunits revealed that a single nonconserved residue in NF-kappaB1 and NF-kappaB2 that corresponds to the P1' residue Arg-41 in p65, prevents cleavage of these subunits by GtgA, GogA, and PipA, explaining the observed substrate specificity of these enzymes. Crystal structures of GtgA in its apo form and in complex with the p65 N-terminal domain explained the importance of the P1' residue. Furthermore, the pattern of interactions suggested that GtgA recognizes NF-kappaB subunits by mimicking the shape and negative charge of the DNA phosphate backbone. Moreover, structure-based mutational analysis of GtgA uncovered amino acids that are required for the interaction of GtgA with p65, as well as those that are required for full activity of GtgA in suppressing NF-kappaB activation. This study therefore provides detailed and critical insight into the mechanism of substrate recognition by this family of proteins important for bacterial virulence.

Structure-function analyses of the bacterial zinc metalloprotease effector protein GtgA uncovers key residues required for deactivating NF-kappaB.,Jennings E, Esposito D, Rittinger K, Thurston TLM J Biol Chem. 2018 Jul 26. pii: RA118.004255. doi: 10.1074/jbc.RA118.004255. PMID:30049795<ref>PMID:30049795</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Lk3 transgenic mice]]
[[Category: Salt1]]
[[Category: Esposito, D]]
[[Category: Jennings, E]]
[[Category: Rittinger, K]]
[[Category: Thurston, T]]
[[Category: Metal binding protein]]
[[Category: Metalloprotease]]
[[Category: Protease]]
[[Category: Zinc]]