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Kothamachu, Varun B.; Feliu, Elisenda; Cardelli, Luca; Soyer, Orkun S. (2015)
Publisher: The Royal Society Publishing
Languages: English
Types: Article
Subjects: QR
The ability to map environmental signals onto distinct internal physiological states or programmes is critical for single-celled microbes. A crucial systems dynamics feature underpinning such ability is multistability. While unlimited multistability is known to arise from multi-site phosphorylation seen in the signalling networks of eukaryotic cells, a similarly universal mechanism has not been identified in microbial signalling systems. These systems are generally known as two-component systems comprising histidine kinase (HK) receptors and response regulator proteins engaging in phosphotransfer reactions. We develop a mathematical framework for analysing microbial systems with multi-domain HK receptors known as hybrid and unorthodox HKs. We show that these systems embed a simple core network that exhibits multistability, thereby unveiling a novel biochemical mechanism for multistability. We further prove that sharing of downstream components allows a system with n multi-domain hybrid HKs to attain 3n steady states. We find that such systems, when sensing distinct signals, can readily implement Boolean logic functions on these signals. Using two experimentally studied examples of two-component systems implementing hybrid HKs, we show that bistability and implementation of logic functions are possible under biologically feasible reaction rates. Furthermore, we show that all sequenced microbial genomes contain significant numbers of hybrid and unorthodox HKs, and some genomes have a larger fraction of these proteins compared with regular HKs. Microbial cells are thus theoretically unbounded in mapping distinct environmental signals onto distinct physiological states and perform complex computations on them. These findings facilitate the understanding of natural two-component systems and allow their engineering through synthetic biology.\ud
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    • into switch-like outputs. Trends Biochem. Sci. 21,
    • 460 - 466. (doi:10.1016/S0968-0004(96)20026-X) 3. Ferrell JE, Machleder EM. 1998 The biochemical
    • oocytes. Science 280, 895 - 898. (doi:10.1126/
    • science.280.5365.895) 4. Pomerening JR, Sontag ED, Ferrell JE. 2003 Building
    • the activation of Cdc2. Nat. Cell Biol. 5, 346 - 351.
    • (doi:10.1038/ncb954) 5. Becskei A, Se´raphin B, Serrano L. 2001 Positive feedback
    • graded to binary response conversion. EMBO J. 20,
    • 2528 - 2535. (doi:10.1093/emboj/20.10.2528) 6. Ozbudak EM, Thattai M, Lim HN, Shraiman BI, van
    • Oudenaarden A. 2004 Multistability in the lactose
    • utilization network of Escherichia coli. Nature 427,
    • 737 - 740. (doi:10.1038/nature02298) 7. Markevich NI, Hoek JB, Kholodenko BN. 2004 Signaling
    • 164, 353 - 359. (doi:10.1083/jcb.200308060) 8. Ortega F, Garce´s JL, Mas F, Kholodenko BN, Cascante
    • M. 2006 Bistability from double phosphorylation in
    • requirements. FEBS J. 273, 3915 - 3926. (doi:10.
    • 1111/j.1742-4658.2006.05394.x) 9. Gardner TS, Cantor CR, Collins JJ. 2000 Construction
    • 403, 339 - 342. (doi:10.1038/35002131) 10. Guet CC, Elowitz MB, Hsing W, Leibler S. 2002
    • 296, 1466 - 1470. (doi:10.1126/science.1067407) 11. O'Shaughnessy EC, Palani S, Collins JJ, Sarkar CA.
    • 2011 Tunable signal processing in synthetic MAP
    • kinase cascades. Cell 144, 119 - 131. (doi:10.1016/j.
    • cell.2010.12.014) 12. Wang L, Sontag ED. 2007 On the number of steady
    • states in a multiple futile cycle. J. Math. Biol. 57,
    • 29 - 52. (doi:10.1007/s00285-007-0145-z) 13. Thomson M, Gunawardena J. 2009 Unlimited
    • Nature 460, 274 - 277. (doi:10.1038/nature08102) 14. Feliu E, Wiuf C. 2012 Enzyme-sharing as a cause of
    • Interface 9, 1224 - 1232. (doi:10.1098/rsif.2011.0664) 15. Holstein K, Flockerzi D, Conradi C. 2013
    • phosphorylation networks. Bull. Math. Biol. 75,
    • 2028 - 2058. (doi:10.1007/s11538-013-9878-6) 16. Stock AM, Robinson VL, Goudreau PN. 2000 Two-
    • component signal transduction. Annu. Rev. Biochem. 69,
    • 183 - 215. (doi:10.1146/annurev.biochem.69.1.183) 17. Amin M, Porter SL, Soyer OS. 2013 Split histidine
    • component signaling networks. PLoS Comput. Biol. 9,
    • e1002949. (doi:10.1371/journal.pcbi.1002949) 18. Tiwari A, Ray JCJ, Narula J, Igoshin OA. 2011
    • 231, 76 - 89. (doi:10.1016/j.mbs.2011.03.004) 19. Hoyle RB, Avitabile D, Kierzek AM. 2012 Equation-
    • PLoS Comput. Biol. 8, e1002396. (doi:10.1371/
    • journal.pcbi.1002396) 20. Dubnau D, Losick R. 2006 Bistability in bacteria.
    • Mol. Microbiol. 61, 564 - 572. (doi:10.1111/j.1365-
    • 2958.2006.05249.x) 21. Maamar H, Raj A, Dubnau D. 2007 Noise in gene
    • Science 317, 526 - 529. (doi:10.1126/science.1140818) 22. Rodrigue A, Quentin Y, Lazdunski A, Me´jean V,
    • Foglino M. 2000 Cell Signalling by oligosaccharides.
    • aeruginosa: why so many? Trends Microbiol. 8,
    • 498 - 504. (doi:10.1016/S0966-842X(00)01833-3) 23. Galperin MY. 2005 A census of membrane-bound and
    • 5, 35. (doi:10.1186/1471-2180-5-35) 24. Narula J, Devi SN, Fujita M, Igoshin OA. 2012
    • decision. Proc. Natl Acad. Sci. USA 109,
    • E3512 - E3522. (doi:10.1073/pnas.1213974109) 25. Alon U, Surette MG, Barkai N, Leibler S. 1999
    • Robustness in bacterial chemotaxis. Nature 397,
    • 168 - 171. (doi:10.1038/16483) 26. Hoch JA. 2000 Two-component and phosphorelay
    • signal transduction. Curr. Opin. Microbiol. 3,
    • 165 - 170. (doi:10.1016/S1369-5274(00)00070-9) 27. Saito H. 2001 Histidine phosphorylation and two-
    • 101, 2497 - 2510. (doi:10.1021/cr000243+) 28. Zhang W, Shi L. 2005 Distribution and evolution of
    • hybrid-type histidine kinases. Microbiology 151,
    • 2159 - 2173. (doi:10.1099/mic.0.279870) 29. Urao T, Yamaguchi-Shinozaki K, Shinozaki K. 2000
    • transduction. Trends Plant Sci. 5, 67 - 74. (doi:10.
    • 1016/S1360-1385(99)01542-3) 30. Janiak-Spens F, Cook PF, West AH. 2005 Kinetic
    • analysis of YPD1-dependent phosphotransfer reactions
    • Biochemistry 44, 377 - 386. (doi:10.1021/bi048433s) 31. Georgellis D, Kwon O, Wulf PD, Lin ECC. 1998 Signal
    • 273, 32 864 - 32 869. (doi:10.1074/jbc.273.49.32864) 32. Bischofs IB, Hug JA, Liu AW, Wolf DM, Arkin AP.
    • 2009 Complexity in bacterial cell - cell
    • phosphorelay. Proc. Natl Acad. Sci. USA 106,
    • 6459 - 6464. (doi:10.1073/pnas.0810878106) 33. Kothamachu VB, Feliu E, Wiuf C, Cardelli L,
    • Soyer OS. 2013 Phosphorelays provide tunable signal
    • processing capabilities for the cell. PLoS Comput. Biol. 9,
    • e1003322. (doi:10.1371/journal.pcbi.1003322) 34. Banaji M, Craciun G. 2009 Graph-theoretic
    • 7, 867 - 900. (doi:10.4310/CMS.2009.v7.n4.a4) 35. Wiuf C, Feliu E. 2013 Power-law kinetics and
    • SIAM J. Appl. Dyn. Syst. 12, 1685 - 1721. (doi:10.
    • 1137/120873388) 36. Long T, Tu KC, Wang Y, Mehta P, Ong NP, Bassler
    • BL, Wingreen NS. 2009 Quantifying the integration
    • resolution. PLoS Biol. 7, e1000068. (doi:10.1371/
    • journal.pbio.1000068) 37. Barakat M, Ortet P, Jourlin-Castelli C, Ansaldi M,
    • Me´jean V, Whitworth DE. 2009 P2CS: a two-
    • transduction research. BMC Genomics 10, 315.
    • (doi:10.1186/1471-2164-10-315) 38. Barakat M, Ortet P, Whitworth DE. 2011 P2CS: a
    • Nucleic Acids Res. 39, D771 - D776. (doi:10.1093/
    • nar/gkq1023) 39. Chen YE, Tsokos CG, Biondi EG, Perchuk BS, Laub MT.
    • 2009 Dynamics of two phosphorelays controlling cell
    • 191, 7417 - 7429. (doi:10.1128/JB.00992-09) 40. Yamamoto K, Hirao K, Oshima T, Aiba H, Utsumi R,
    • Ishihama A. 2005 Functional characterization in vitro
    • from Escherichia coli. J. Biol. Chem. 280,
    • 1448 - 1456. (doi:10.1074/jbc.M410104200) 41. Rowland MA, Deeds EJ. 2014 Crosstalk and the
    • Proc. Natl Acad. Sci. USA 111, 5550 - 5555. (doi:10.
    • 1073/pnas.1317178111) 42. Guckes KR, Kostakioti M, Breland EJ, Gu AP, Shaffer
    • 2013 Strong cross-system interactions drive the
    • USA 110, 16 592 - 16 597. (doi:10.1073/pnas.
    • 1315320110) 43. Whitaker WR, Davis SA, Arkin AP, Dueber JE. 2012
    • Proc. Natl Acad. Sci. USA 109, 18 090 - 18 095.
    • (doi:10.1073/pnas.1209230109) 44. Levskaya A et al. 2005 Synthetic biology: engineering
    • Escherichia coli to see light. Nature 438, 441 - 442.
    • (doi:10.1038/nature04405) 45. West AH, Stock AM. 2001 Histidine kinases and
    • signaling systems. Trends Biochem. Sci. 26,
    • 369 - 376. (doi:10.1016/S0968-0004(01)01852-7) 46. Kim J-R, Cho K-H. 2006 The multi-step
    • Comput. Biol. Chem. 30, 438 - 444. (doi:10.1016/j.
    • compbiolchem.2006.09.004) 47. Joshi B, Shiu A. 2013 Atoms of multistationarity in
    • chemical reaction networks. J. Math. Chem. 51,
    • 153 - 178. (doi:10.1007/s10910-012-0072-0) 48. Feliu E, Wiuf C. 2013 Simplifying biochemical
    • Interface 10, 20130484. (doi:10.1098/rsif.2013.0484) 9
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