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5k98

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Revision as of 02:29, 13 July 2016

Structure of HipA-HipB-O2-O3 complex

Structural highlights

5k98 is a 6 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[HIPA_ECOLI] Toxic component of a toxin-antitoxin (TA) module. Autophosphorylates (Ser-150) and phosphorylates EF-Tu in vitro (on 'Thr-383'), may act on other proteins as well. The hipA7 mutation leads to increased generation of persister cells, cells that survive antibiotic treatment probably by entering into a dormant state. Wild-type cells produce persisters at a frequency of 10-6 to 10-5 whereas mutant hipA7 cells produce persisters at a frequency of 10-2. Generation of persister cells requires (p)ppGpp as cells lacking relA or relA/spoT generate fewer or no persister cells respectively compared to hipA7. Low level expression of HipA causes cell filamentation and depending on the protein level is toxic enough to reduce cell growth or even kill cells. Expression of wild-type HipA also leads to high antibiotic tolerance of the survivor cells. The toxic effect of HipA is neutralized by its cognate antitoxin HipB. With HipB acts as a corepressor for transcription of the hipBA promoter.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Multidrug tolerance is largely responsible for chronic infections and caused by a small population of dormant cells called persisters. Selection for survival in the presence of antibiotics produced the first genetic link to multidrug tolerance: a mutant in the Escherichia coli hipA locus. HipA encodes a serine-protein kinase, the multidrug tolerance activity of which is neutralized by binding to the transcriptional regulator HipB and hipBA promoter. The physiological role of HipA in multidrug tolerance, however, has been unclear. Here we show that wild-type HipA contributes to persister formation and that high-persister hipA mutants cause multidrug tolerance in urinary tract infections. Perplexingly, high-persister mutations map to the N-subdomain-1 of HipA far from its active site. Structures of higher-order HipA-HipB-promoter complexes reveal HipA forms dimers in these assemblies via N-subdomain-1 interactions that occlude their active sites. High-persistence mutations, therefore, diminish HipA-HipA dimerization, thereby unleashing HipA to effect multidrug tolerance. Thus, our studies reveal the mechanistic basis of heritable, clinically relevant antibiotic tolerance.

HipBA-promoter structures reveal the basis of heritable multidrug tolerance.,Schumacher MA, Balani P, Min J, Chinnam NB, Hansen S, Vulic M, Lewis K, Brennan RG Nature. 2015 Aug 6;524(7563):59-64. doi: 10.1038/nature14662. Epub 2015 Jul 29. PMID:26222023^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Correia FF, D'Onofrio A, Rejtar T, Li L, Karger BL, Makarova K, Koonin EV, Lewis K. Kinase activity of overexpressed HipA is required for growth arrest and multidrug tolerance in Escherichia coli. J Bacteriol. 2006 Dec;188(24):8360-7. Epub 2006 Oct 13. PMID:17041039 doi:10.1128/JB.01237-06
↑ Moyed HS, Bertrand KP. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol. 1983 Aug;155(2):768-75. PMID:6348026
↑ Black DS, Irwin B, Moyed HS. Autoregulation of hip, an operon that affects lethality due to inhibition of peptidoglycan or DNA synthesis. J Bacteriol. 1994 Jul;176(13):4081-91. PMID:8021189
↑ Korch SB, Henderson TA, Hill TM. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol Microbiol. 2003 Nov;50(4):1199-213. PMID:14622409
↑ Schumacher MA, Piro KM, Xu W, Hansen S, Lewis K, Brennan RG. Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB. Science. 2009 Jan 16;323(5912):396-401. PMID:19150849 doi:323/5912/396
↑ Schumacher MA, Balani P, Min J, Chinnam NB, Hansen S, Vulic M, Lewis K, Brennan RG. HipBA-promoter structures reveal the basis of heritable multidrug tolerance. Nature. 2015 Aug 6;524(7563):59-64. doi: 10.1038/nature14662. Epub 2015 Jul 29. PMID:26222023 doi:http://dx.doi.org/10.1038/nature14662

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5k98"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[5k98]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K98 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K98 FirstGlance]. <br>
 </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=5k98 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k98 OCA], [http://pdbe.org/5k98 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k98 RCSB], [http://www.ebi.ac.uk/pdbsum/5k98 PDBsum]</span></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=5k98 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k98 OCA], [http://pdbe.org/5k98 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k98 RCSB], [http://www.ebi.ac.uk/pdbsum/5k98 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k98 ProSAT]</span></td></tr>
 </table>
 == Function ==

5k98

From Proteopedia

Revision as of 02:29, 13 July 2016

Structure of HipA-HipB-O2-O3 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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