| Structural highlights
3tpv is a 1 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| NonStd Res: | |
| Related: | 3dnt, 3dnu, 3dnv, 3fbr, 3hzi, 3tpb, 3tpd, 3tpe, 3tpt |
| Gene: | hipA (Escherichia coli) |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
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
HipA is a bacterial serine/threonine protein kinase that phosphorylates targets, bringing about persistence and multidrug tolerance. Autophosphorylation of residue Ser150 is a critical regulatory mechanism of HipA function. Intriguingly, Ser150 is not located on the activation loop, as are other kinases; instead, it is in the protein core, where it forms part of the ATP-binding "P loop motif." How this buried residue is phosphorylated and regulates kinase activity is unclear. Here, we report multiple structures that reveal the P loop motif's exhibition of a remarkable "in-out" conformational equilibrium, which allows access to Ser150 and its intermolecular autophosphorylation. Phosphorylated Ser150 stabilizes the "out state," which inactivates the kinase by disrupting the ATP-binding pocket. Thus, our data reveal a mechanism of protein kinase regulation that is vital for multidrug tolerance and persistence, as kinase inactivation provides the critical first step in allowing dormant cells to revert to the growth phenotype and to reinfect the host.
Role of Unusual P Loop Ejection and Autophosphorylation in HipA-Mediated Persistence and Multidrug Tolerance.,Schumacher MA, Min J, Link TM, Guan Z, Xu W, Ahn YH, Soderblom EJ, Kurie JM, Evdokimov A, Moseley MA, Lewis K, Brennan RG Cell Rep. 2012 Sep 27;2(3):518-25. doi: 10.1016/j.celrep.2012.08.013. Epub 2012, Sep 20. PMID:22999936[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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, Min J, Link TM, Guan Z, Xu W, Ahn YH, Soderblom EJ, Kurie JM, Evdokimov A, Moseley MA, Lewis K, Brennan RG. Role of Unusual P Loop Ejection and Autophosphorylation in HipA-Mediated Persistence and Multidrug Tolerance. Cell Rep. 2012 Sep 27;2(3):518-25. doi: 10.1016/j.celrep.2012.08.013. Epub 2012, Sep 20. PMID:22999936 doi:http://dx.doi.org/10.1016/j.celrep.2012.08.013
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