title: Modeling chemotaxis reveals the role of reversed phosphotransfer and a bi-functional kinase-phosphatase.
abstract: Understanding how multiple signals are integrated in living cells to produce a balanced response is a major challenge in biology. Two-component signal transduction pathways, such as bacterial chemotaxis, comprise histidine protein kinases (HPKs) and response regulators (RRs). These are used to sense and respond to changes in the environment. Rhodobacter sphaeroides has a complex chemosensory network with two signaling clusters, each containing a HPK, CheA. Here we demonstrate, using a mathematical model, how the outputs of the two signaling clusters may be integrated. We use our mathematical model supported by experimental data to predict that: (1) the main RR controlling flagellar rotation, CheY(6), aided by its specific phosphatase, the bifunctional kinase CheA(3), acts as a phosphate sink for the other RRs; and (2) a phosphorelay pathway involving CheB(2) connects the cytoplasmic cluster kinase CheA(3) with the polar localised kinase CheA(2), and allows CheA(3)-P to phosphorylate non-cognate chemotaxis RRs. These two mechanisms enable the bifunctional kinase/phosphatase activity of CheA(3) to integrate and tune the sensory output of each signaling cluster to produce a balanced response. The signal integration mechanisms identified here may be widely used by other bacteria, since like R. sphaeroides, over 50% of chemotactic bacteria have multiple cheA homologues and need to integrate signals from different sources.
authors.affiliation: Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, United Kingdom. m.tindall@reading.ac.uk
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Tindall
authors.forename: Steven L
authors.initials: SL
authors.lastname: Porter
authors.forename: Philip K
authors.initials: PK
authors.lastname: Maini
authors.forename: Judith P
authors.initials: JP
authors.lastname: Armitage
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D005407:Flagella / Q000201:enzymology / Q000502:physiology; D000071677:Histidine Kinase; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D012242:Rhodobacter sphaeroides / Q000201:enzymology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; D011494:Protein Kinases; D000071677:Histidine Kinase; D010744:Phosphoric Monoester Hydrolases
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18531-6
references.pmid: 19020080
references.citation: J Biol Chem. 2008 Jan 11;283(2):756-65
references.pmid: 17998207
references.citation: Nature. 1988 Nov 10;336(6195):139-43
references.pmid: 3185734
references.citation: Nature. 1999 Jan 14;397(6715):168-71
references.pmid: 9923680
references.citation: Mol Microbiol. 2010 Apr;76(2):318-30
references.pmid: 20525091
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17181-6
references.pmid: 19805102
references.citation: BMC Syst Biol. 2010 Jan 11;4:3
references.pmid: 20064255
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11582-7
references.pmid: 19571004
references.citation: Mol Microbiol. 2005 Jun;56(5):1358-72
references.pmid: 15882426
references.citation: J Bacteriol. 2006 Mar;188(5):1691-700
references.pmid: 16484180
references.citation: Mol Microbiol. 2008 Jul;69(2):453-65
references.pmid: 18557815
references.citation: J Bacteriol. 2004 Aug;186(15):5172-7
references.pmid: 15262956
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):123-7
references.pmid: 11742065
references.citation: Mol Microbiol. 1998 Feb;27(3):573-85
references.pmid: 9489669
references.citation: EMBO J. 2000 Sep 1;19(17):4601-13
references.pmid: 10970853
references.citation: Science. 2000 Mar 3;287(5458):1652-5
references.pmid: 10698740
references.citation: J Biol Chem. 2004 Dec 24;279(52):54573-80
references.pmid: 15485885
references.citation: PLoS Biol. 2004 Feb;2(2):E49
references.pmid: 14966542
references.citation: Microbiology (Reading). 2005 Oct;151(Pt 10):3299-3311
references.pmid: 16207913
references.citation: Prog Biophys Mol Biol. 2009 Sep-Oct;100(1-3):40-6
references.pmid: 19540260
references.citation: Proc Natl Acad Sci U S A. 1989 Feb;86(4):1208-12
references.pmid: 2645576
references.citation: Methods Enzymol. 2007;423:392-413
references.pmid: 17609142
references.citation: Science. 1993 Mar 19;259(5102):1717-23
references.pmid: 8456299
references.citation: J Bacteriol. 2005 Jan;187(1):54-64
references.pmid: 15601688
references.citation: J Bacteriol. 2001 Dec;183(24):7135-44
references.pmid: 11717272
references.citation: PLoS Biol. 2009 Jun 16;7(6):e1000137
references.pmid: 19547746
references.citation: Proc Natl Acad Sci U S A. 1990 Jan;87(1):41-5
references.pmid: 2404281
references.citation: Trends Biochem Sci. 2008 Jan;33(1):9-19
references.pmid: 18165013
references.citation: Cell. 1988 Apr 8;53(1):79-87
references.pmid: 3280143
references.citation: Cell. 1996 Sep 20;86(6):845-8
references.pmid: 8808618
references.citation: Trends Microbiol. 2008 Jun;16(6):251-60
references.pmid: 18440816
references.citation: Appl Environ Microbiol. 2009 Oct;75(20):6613-5
references.pmid: 19684165
references.citation: Genes Dev. 2008 Oct 1;22(19):2601-11
references.pmid: 18832064
references.citation: J Immunol Methods. 1995 Mar 27;180(2):213-8
references.pmid: 7714335
references.citation: Mol Microbiol. 2003 Nov;50(3):763-70
references.pmid: 14617139
references.citation: J Mol Biol. 2009 Apr 24;388(1):71-84
references.pmid: 19358329
references.citation: PLoS Biol. 2010 Feb 09;8(2):e1000306
references.pmid: 20161720
references.citation: Sci Signal. 2010 Jun 29;3(128):ra50
references.pmid: 20587806
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8787-91
references.pmid: 8415608
references.citation: BMC Syst Biol. 2009 Oct 31;3:105
references.pmid: 19878602
references.citation: Mol Microbiol. 2002 Dec;46(5):1211-21
references.pmid: 12453209
references.citation: Mol Biosyst. 2009 Dec;5(12):1853-9
references.pmid: 19768197
references.citation: Biochemistry. 1998 Feb 24;37(8):2327-35
references.pmid: 9485379
references.citation: J Bacteriol. 1987 Feb;169(2):514-8
references.pmid: 3492489
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11509-14
references.pmid: 16864771
references.citation: J Biol Chem. 1989 Dec 25;264(36):21770-8
references.pmid: 2689446
references.citation: Nat Rev Mol Cell Biol. 2004 Dec;5(12):1024-37
references.pmid: 15573139
references.citation: Microbiol Mol Biol Rev. 2004 Jun;68(2):301-19
references.pmid: 15187186
references.citation: Mol Microbiol. 2002 Nov;46(4):1081-94
references.pmid: 12421313
references.citation: Mol Microbiol. 2001 Jun;40(6):1261-72
references.pmid: 11442826
references.citation: J Bacteriol. 2007 Apr;189(8):3208-16
references.pmid: 17293429
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14855-60
references.pmid: 18812513
references.citation: J Mol Biol. 2002 Nov 15;324(1):35-45
references.pmid: 12421557
references.citation: J Biol Chem. 1991 May 25;266(15):9764-70
references.pmid: 1851755
references.citation: J Biol Chem. 2006 Oct 27;281(43):32694-704
references.pmid: 16950782
references.citation: Bull Math Biol. 2008 Aug;70(6):1525-69
references.pmid: 18642048
references.citation: Cell. 1994 Dec 16;79(6):1047-55
references.pmid: 8001132
references.citation: Mol Microbiol. 2000 Jan;35(1):101-12
references.pmid: 10632881
references.citation: Biophys J. 2000 Mar;78(3):1207-15
references.pmid: 10692310
references.citation: Mol Microbiol. 2006 Apr;60(2):525-34
references.pmid: 16573700
references.citation: J Biol Chem. 1989 Oct 15;264(29):17337-42
references.pmid: 2677005
references.citation: Mol Syst Biol. 2008;4:211
references.pmid: 18682701
references.citation: PLoS Comput Biol. 2008 Jan;4(1):e1
references.pmid: 18179279
references.citation: J Bacteriol. 2007 Nov;189(22):8397-401
references.pmid: 17890312
references.citation: Annu Rev Biochem. 2000;69:183-215
references.pmid: 10966457
references.citation: Nature. 1998 May 7;393(6680):85-8
references.pmid: 9590695
references.citation: Bull Math Biol. 2008 Aug;70(6):1570-607
references.pmid: 18642047