title: Cys-scanning disulfide crosslinking and bayesian modeling probe the transmembrane signaling mechanism of the histidine kinase, PhoQ.
abstract: Bacteria transduce signals across the membrane using two-component systems (TCSs), consisting of a membrane-spanning sensor histidine kinase and a cytoplasmic response regulator. In gram-negative bacteria, the PhoPQ TCS senses cations and antimicrobial peptides, yet little is known about the structural changes involved in transmembrane signaling. We construct a model of PhoQ signal transduction using Bayesian inference, based on disulfide crosslinking data and homologous crystal structures. The data are incompatible with a single conformation but are instead consistent with two interconverting structures. These states differ in membrane depth of the periplasmic acidic patch and the reciprocal displacement of diagonal helices along the dimer interface. Studies of multiple histidine kinases suggest this repacking might be a common mode of signal transduction in sensor His-kinase receptors. Because a similar scissors model has been ruled out in CheA-linked chemoreceptors, the evidence suggests that sensor His-kinase and CheA-linked receptors possess different signaling mechanisms.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group19104, USA, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Molnar
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonomi
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pellarin
authors.affiliation: Pharmacological Sciences Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Graham D
authors.initials: GD
authors.lastname: Clinthorne
authors.affiliation: Biochemistry and Molecular Biophysics Graduate Group19104, USA, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gonzalez
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shalom D
authors.initials: SD
authors.lastname: Goldberg
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Goulian
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.affiliation: Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: william.degrado@ucsf.edu.
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000502:physiology; D001499:Bayes Theorem; D003198:Computer Simulation; D003553:Cystine / Q000737:chemistry*; D000071677:Histidine Kinase; D008958:Models, Molecular; D011494:Protein Kinases / Q000737:chemistry* / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein
chemical_list: D001426:Bacterial Proteins; C079792:PhoQ protein, Bacteria; D003553:Cystine; D011494:Protein Kinases; D000071677:Histidine Kinase
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16185-90
references.pmid: 19805278
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: Structure. 2013 Jul 2;21(7):1127-36
references.pmid: 23746806
references.citation: Protein Pept Lett. 2010 Nov;17(11):1383-91
references.pmid: 20594156
references.citation: Proc Natl Acad Sci U S A. 1992 May 1;89(9):4144-8
references.pmid: 1315053
references.citation: J Mol Biol. 2006 Mar 10;356(5):1193-206
references.pmid: 16406409
references.citation: PLoS Comput Biol. 2013;9(1):e1002878
references.pmid: 23359663
references.citation: J Bacteriol. 1999 Sep;181(17):5309-16
references.pmid: 10464202
references.citation: Protein Sci. 2002 Jun;11(6):1472-81
references.pmid: 12021446
references.citation: Curr Opin Struct Biol. 1999 Aug;9(4):500-8
references.pmid: 10449377
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: Mol Microbiol. 1999 Nov;34(4):633-40
references.pmid: 10564504
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10131-6
references.pmid: 11504917
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):E1733-42
references.pmid: 22670053
references.citation: Cell. 2006 Sep 8;126(5):929-40
references.pmid: 16959572
references.citation: Trends Biochem Sci. 2001 Apr;26(4):257-65
references.pmid: 11295559
references.citation: Nature. 2007 Nov 29;450(7170):695-701
references.pmid: 18046406
references.citation: PLoS Genet. 2009 Dec;5(12):e1000788
references.pmid: 20041203
references.citation: PLoS Biol. 2014 Jan 28;12(1):e1001776
references.pmid: 24492262
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):E1481-8
references.pmid: 22556268
references.citation: J Mol Biol. 2009 Oct 2;392(4):1087-101
references.pmid: 19527732
references.citation: FEMS Microbiol Lett. 2001 Sep 11;203(1):11-21
references.pmid: 11557134
references.citation: J Bacteriol. 1996 Sep;178(17):5092-9
references.pmid: 8752324
references.citation: Nat Struct Biol. 2000 Aug;7(8):626-33
references.pmid: 10932244
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1756-61
references.pmid: 16446450
references.citation: Mol Microbiol. 2009 Sep;73(5):801-14
references.pmid: 19656294
references.citation: Biochemistry. 1995 Mar 7;34(9):3048-55
references.pmid: 7893717
references.citation: J Biol Chem. 1996 Oct 25;271(43):26630-6
references.pmid: 8900137
references.citation: J Mol Biol. 2008 Oct 31;383(1):49-61
references.pmid: 18725229
references.citation: Nature. 2002 Oct 3;419(6906):484-7
references.pmid: 12368857
references.citation: Cell. 2009 Oct 16;139(2):325-36
references.pmid: 19800110
references.citation: J Bacteriol. 2005 Mar;187(6):2182-9
references.pmid: 15743967
references.citation: Protein Eng. 1998 Sep;11(9):739-47
references.pmid: 9796821
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11546-51
references.pmid: 8876172
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6298-305
references.pmid: 10841536
references.citation: J Mol Biol. 2010 Apr 16;397(5):1156-74
references.pmid: 20184894
references.citation: Microbiol Mol Biol Rev. 2006 Dec;70(4):910-38
references.pmid: 17158704
references.citation: J Biol Chem. 2008 May 16;283(20):13762-70
references.pmid: 18348979
references.citation: Annu Rev Microbiol. 2012;66:285-303
references.pmid: 22994495
references.citation: PLoS Biol. 2012 Jan;10(1):e1001244
references.pmid: 22272186
references.citation: Structure. 2012 Jan 11;20(1):56-66
references.pmid: 22244755
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10902-7
references.pmid: 20498088
references.citation: Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10402-6
references.pmid: 1660136
references.citation: J Mol Biol. 1992 Aug 20;226(4):1219-35
references.pmid: 1518053
references.citation: Mol Microbiol. 1999 Aug;33(4):858-72
references.pmid: 10447894
references.citation: Cell. 1996 Jan 12;84(1):165-74
references.pmid: 8548821
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2545-50
references.pmid: 8637911
references.citation: Mol Microbiol. 2012 Jul;85(2):299-313
references.pmid: 22651704
references.citation: Structure. 2012 Apr 4;20(4):729-41
references.pmid: 22483119
references.citation: Trends Biochem Sci. 2013 Nov;38(11):538-45
references.pmid: 24051046
references.citation: PLoS Biol. 2013;11(2):e1001493
references.pmid: 23468592
references.citation: Structure. 2009 Sep 9;17(9):1195-204
references.pmid: 19748340
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):959-63
references.pmid: 14732697
references.citation: Antimicrob Agents Chemother. 2007 Dec;51(12):4374-81
references.pmid: 17938183
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8141-6
references.pmid: 20404199
references.citation: J Biol Chem. 1995 Oct 13;270(41):24043-53
references.pmid: 7592603
references.citation: J Biol Chem. 1993 May 5;268(13):9787-92
references.pmid: 8486661
references.citation: Biochemistry. 1995 Aug 1;34(30):9722-33
references.pmid: 7626643
references.citation: Structure. 2009 Feb 13;17(2):190-201
references.pmid: 19217390
references.citation: Annu Rev Biochem. 2000;69:183-215
references.pmid: 10966457
references.citation: Science. 2005 Jul 8;309(5732):303-6
references.pmid: 16002620
references.citation: Proc Natl Acad Sci U S A. 1989 Jul;86(13):5054-8
references.pmid: 2544889
references.citation: Proc Natl Acad Sci U S A. 2012 May 8;109(19):7298-303
references.pmid: 22532667
references.citation: Science. 1991 Nov 29;254(5036):1342-7
references.pmid: 1660187
references.citation: J Bacteriol. 1974 Sep;119(3):736-47
references.pmid: 4604283
references.citation: J Mol Biol. 2008 Jun 13;379(4):656-65
references.pmid: 18468622