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Signal transduction mechanisms in heme-based globin-coupled oxygen sensors with a focus on a histidine kinase (AfGcHK) and a diguanylate cyclase (YddV or EcDosC)

  • Jakub Vávra ORCID logo , Artur Sergunin , Petr Jeřábek ORCID logo , Toru Shimizu ORCID logo and Markéta Martínková ORCID logo EMAIL logo
Published/Copyright: September 27, 2022
Biological Chemistry
From the journal Biological Chemistry Volume 403 Issue 11-12

Abstract

Heme is a vital cofactor of proteins with roles in oxygen transport (e.g. hemoglobin), storage (e.g. myoglobin), and activation (e.g. P450) as well as electron transfer (e.g. cytochromes) and many other functions. However, its structural and functional role in oxygen sensing proteins differs markedly from that in most other enzymes, where it serves as a catalytic or functional center. This minireview discusses the mechanism of signal transduction in two heme-based oxygen sensors: the histidine kinase AfGcHK and the diguanylate cyclase YddV (EcDosC), both of which feature a heme-binding domain containing a globin fold resembling that of hemoglobin and myoglobin.

Keywords: globin-coupled sensors; heme; heme-based sensor proteins; hemoproteins; oxygen sensors; signal transduction
Corresponding author: Markéta Martínková, Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, 128 43 Prague 2, Czech Republic, E-mail:

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: Supported by the grant 8F20011 from The Ministry of Education, Youth and Sports and the GA UK 158120 project from the Charles University.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

Anzenbacher, P., Marchal, S., Palacký, J., Anzenbacherová, E., Domaschke, T., Lange, R., Shimizu, T., Kitanishi, K., Stranava, M., Stiborová, M., et al.. (2014). Pressure effects reveal that changes in the redox states of the heme iron complexes in the sensor domains of two heme-based oxygen sensor proteins, EcDOS and YddV, have profound effects on their flexibility. FEBS J. 281: 5208–5219, https://doi.org/10.1111/febs.13060.Search in Google Scholar PubMed

Bourret, R.B., Kennedy, E.N., Foster, C.A., Sepúlveda, V.E., and Goldman, W.E. (2021). A radical reimagining of fungal two-component regulatory systems. Trends Microbiol. 29: 883–893, https://doi.org/10.1016/j.tim.2021.03.005.Search in Google Scholar PubMed PubMed Central

Coburger, I., Yang, K., Bernert, A., Wiesel, E., Sahoo, N., Swain, S.M., Hoshi, T., Schönherr, R., and Heinemann, S.H. (2020). Impact of intracellular hemin on N-type inactivation of voltage-gated K+ channels. Pflügers Arch. 472: 551–560, https://doi.org/10.1007/s00424-020-02386-1.Search in Google Scholar PubMed PubMed Central

de França Lopes, L.G., Júnior, F.S.G., Holanda, A.K.M., de Carvalho, I.M.M., Longhinotti, E., Paulo, T.F., Abreu, D.S., Bernhardt, P.V., Gilles-Gonzalez, M.-A., Diógenes, I.C.N., et al.. (2021). Bioinorganic systems responsive to the diatomic gases O2, NO, and CO: from biological sensors to therapy. Coord. Chem. Rev. 445: 214096, https://doi.org/10.1016/j.ccr.2021.214096.Search in Google Scholar

Dimitrov, J.D. and Roumenina, L.T. (2021). Heme: driver of erythrocyte elimination. Blood 138: 1092–1094, https://doi.org/10.1182/blood.2021012875.Search in Google Scholar PubMed

Donegan, R.K., Moore, C.M., Hanna, D.A., and Reddi, A.R. (2019). Handling heme: the mechanisms underlying the movement of heme within and between cells. Free Radic. Biol. Med. 133: 88–100, https://doi.org/10.1016/j.freeradbiomed.2018.08.005.Search in Google Scholar PubMed PubMed Central

Du, Y., Liu, G., Yan, Y., Huang, D., Luo, W., Martinkova, M., Man, P., and Shimizu, T. (2013). Conversion of a heme-based oxygen sensor to a heme oxygenase by hydrogen sulfide: effects of mutations in the heme distal side of a heme-based oxygen sensor phosphodiesterase (Ec DOS). Biometals 26: 839–852, https://doi.org/10.1007/s10534-013-9640-4.Search in Google Scholar PubMed

Fleischhacker, A.S., Sarkar, A., Liu, L., and Ragsdale, S.W. (2022). Regulation of protein function and degradation by heme, heme responsive motifs, and CO. Crit. Rev. Biochem. Mol. Biol. 57: 16–47, doi:https://doi.org/10.1080/10409238.2021.1961674.Search in Google Scholar PubMed PubMed Central

Fojtikova, V., Bartosova, M., Man, P., Stranava, M., Shimizu, T., and Martinkova, M. (2016). Effects of hydrogen sulfide on the heme coordination structure and catalytic activity of the globin-coupled oxygen sensor AfGcHK. Biometals 29: 715–729, https://doi.org/10.1007/s10534-016-9947-z.Search in Google Scholar PubMed

Fojtikova, V., Stranava, M., Vos, M.H., Liebl, U., Hranicek, J., Kitanishi, K., Shimizu, T., and Martinkova, M. (2015). Kinetic analysis of a globin-coupled histidine kinase, AfGcHK: effects of the heme iron complex, response regulator, and metal cations on autophosphorylation activity. Biochemistry 54: 5017–5029, https://doi.org/10.1021/acs.biochem.5b00517.Search in Google Scholar PubMed

Gallio, A.E., Fung, S.S.P., Cammack-Najera, A., Hudson, A.J., and Raven, E.L. (2021). Understanding the logistics for the distribution of heme in cells. JACS Au 1: 1541–1555, https://doi.org/10.1021/jacsau.1c00288.Search in Google Scholar PubMed PubMed Central

Hammerschmid, D., Germani, F., Drusin, S.I., Fagnen, C., Schuster, C.D., Hoogewijs, D., Marti, M.A., Venien-Bryan, C., Moens, L., Van Doorslaer, S., et al.. (2021). Structural modeling of a novel membrane-bound globin-coupled sensor in Geobacter sulfurreducens. Comput. Struct. Biotechnol. J. 19: 1874–1888, https://doi.org/10.1016/j.csbj.2021.03.031.Search in Google Scholar PubMed PubMed Central

Hanna, D.A., Moore, C.M., Liu, L., Yuan, X., Dominic, I.M., Fleischhacker, A.S., Hamza, I., Ragsdale, S.W., and Reddi, A.R. (2022). Heme oxygenase-2 (HO-2) binds and buffers labile ferric heme in human embryonic kidney cells. J. Biol. Chem. 298: 101549, https://doi.org/10.1016/j.jbc.2021.101549.Search in Google Scholar PubMed PubMed Central

Hopp, M.T. and Imhof, D. (2021). Linking labile heme with thrombosis. J. Clin. Med. 10: 427, https://doi.org/10.3390/jcm10030427.Search in Google Scholar PubMed PubMed Central

Igarashi, J., Murase, M., Iizuka, A., Pichierri, F., Martinkova, M., and Shimizu, T. (2008). Elucidation of the heme binding site of heme-regulated eukaryotic initiation factor 2alpha kinase and the role of the regulatory motif in heme sensing by spectroscopic and catalytic studies of mutant proteins. J. Biol. Chem. 283: 18782–18791, https://doi.org/10.1074/jbc.m801400200.Search in Google Scholar

Kitanishi, K., Kobayashi, K., Uchida, T., Ishimori, K., Igarashi, J., and Shimizu, T. (2011). Identification and functional and spectral characterization of a globin-coupled histidine kinase from Anaeromyxobacter sp. Fw109-5. J. Biol. Chem. 286: 35522–35534, https://doi.org/10.1074/jbc.m111.274811.Search in Google Scholar

Kitanishi, K., Shimonaka, M., and Unno, M. (2021). Characterization of a cobalt-substituted globin-coupled oxygen sensor histidine kinase from anaeromyxobacter sp. fw109-5: insights into catalytic regulation by its heme coordination structure. ACS Omega 6: 34912–34919, https://doi.org/10.1021/acsomega.1c05564.Search in Google Scholar PubMed PubMed Central

Krol, E., Schäper, S., and Becker, A. (2020). Cyclic di-GMP signaling controlling the free-living lifestyle of alpha-proteobacterial rhizobia. Biol. Chem. 401: 1335–1348, https://doi.org/10.1515/hsz-2020-0232.Search in Google Scholar PubMed

Krüger, A., Keppel, M., Sharma, V., and Frunzke, J. (2022). The diversity of heme sensor systems – heme-responsive transcriptional regulation mediated by transient heme protein interactions. FEMS Microbiol. Rev. 46: fuac002, doi:https://doi.org/10.1093/femsre/fuac002.Search in Google Scholar PubMed

Kühl, T. and Imhof, D. (2014). Regulatory Fe(II/III) heme: the reconstruction of a molecule’s biography. Chembiochem 15: 2024–2035, https://doi.org/10.1002/cbic.201402218.Search in Google Scholar PubMed

Kunz, S. and Graumann, P.L. (2020). Spatial organization enhances versatility and specificity in cyclic di-GMP signaling. Biol. Chem. 401: 1323–1334, https://doi.org/10.1515/hsz-2020-0202.Search in Google Scholar PubMed

Lambry, J.C., Stranava, M., Lobato, L., Martinkova, M., Shimizu, T., Liebl, U., and Vos, M.H. (2016). Ultrafast spectroscopy evidence for picosecond ligand exchange at the binding site of a heme protein: heme-based sensor YddV. J. Phys. Chem. Lett. 7: 69–74, https://doi.org/10.1021/acs.jpclett.5b02517.Search in Google Scholar PubMed

Lengalova, A., Fojtikova-Proskova, V., Vavra, J., Martínek, V., Stranava, M., Shimizu, T., and Martinkova, M. (2019). Kinetic analysis of a globin-coupled diguanylate cyclase, YddV: effects of heme iron redox state, axial ligands, and heme distal mutations on catalysis. J. Inorg. Biochem. 201: 110833, https://doi.org/10.1016/j.jinorgbio.2019.110833.Search in Google Scholar PubMed

Martínková, M., Kitanishi, K., and Shimizu, T. (2013). Heme-based globin-coupled oxygen sensors: linking oxygen binding to functional regulation of diguanylate cyclase, histidine kinase, and methyl-accepting chemotaxis. J. Biol. Chem. 288: 27702–27711, https://doi.org/10.1074/jbc.r113.473249.Search in Google Scholar PubMed PubMed Central

Miksanova, M., Igarashi, J., Minami, M., Sagami, I., Yamauchi, S., Kurokawa, H., and Shimizu, T. (2006). Characterization of heme-regulated eIF2alpha kinase: roles of the N-terminal domain in the oligomeric state, heme binding, catalysis, and inhibition. Biochemistry 45: 9894–9905, https://doi.org/10.1021/bi060556k.Search in Google Scholar PubMed

Négrerie, M. (2019). Iron transitions during activation of allosteric heme proteins in cell signaling. Metallomics 11: 868–893, https://doi.org/10.1039/c8mt00337h.Search in Google Scholar PubMed

Patterson, D.C., Ruiz, M.P., Yoon, H., Walker, J.A., Armache, J.P., Yennawar, N.H., and Weinert, E.E. (2021). Differential ligand-selective control of opposing enzymatic activities within a bifunctional c-di-GMP enzyme. Proc. Natl. Acad. Sci. U. S. A. 118: e2100657118, https://doi.org/10.1073/pnas.2100657118.Search in Google Scholar PubMed PubMed Central

Pavlou, A., Martínková, M., Shimizu, T., Kitanishi, K., Stranava, M., Loullis, A., and Pinakoulaki, E. (2015). Probing the ligand recognition and discrimination environment of the globin-coupled oxygen sensor protein YddV by FTIR and time-resolved step-scan FTIR spectroscopy. Phys. Chem. Chem. Phys. 17: 17007–17015, https://doi.org/10.1039/c5cp01708d.Search in Google Scholar PubMed

Pradhan, P., Vijayan, V., Gueler, F., and Immenschuh, S. (2020). Interplay of heme with macrophages in homeostasis and inflammation. Int. J. Mol. Sci. 21: E740, https://doi.org/10.3390/ijms21030740.Search in Google Scholar PubMed PubMed Central

Randall, T.E., Eckartt, K., Kakumanu, S., Price-Whelan, A., Dietrich, L.E.P., and Harrison, J.J. (2022). Sensory perception in bacterial cyclic diguanylate signal transduction. J. Bacteriol. 204: e0043321, https://doi.org/10.1128/JB.00433-21.Search in Google Scholar PubMed PubMed Central

Schödel, J. and Ratcliffe, P.J. (2019). Mechanisms of hypoxia signalling: new implications for nephrology. Nat. Rev. Nephrol. 15: 641–659, https://doi.org/10.1038/s41581-019-0182-z.Search in Google Scholar PubMed

Shimizu, T., Huang, D., Yan, F., Stranava, M., Bartosova, M., Fojtíková, V., and Martínková, M. (2015). Gaseous O2, NO, and CO in signal transduction: structure and function relationships of heme-based gas sensors and heme-redox sensors. Chem. Rev. 115: 6491–6533, https://doi.org/10.1021/acs.chemrev.5b00018.Search in Google Scholar PubMed

Shimizu, T., Lengalova, A., Martínek, V., and Martínková, M. (2019). Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres. Chem. Soc. Rev. 48: 5624–5657, https://doi.org/10.1039/c9cs00268e.Search in Google Scholar PubMed

Skalova, T., Lengalova, A., Dohnalek, J., Harlos, K., Mihalcin, P., Kolenko, P., Stranava, M., Blaha, J., Shimizu, T., and Martínková, M. (2020). Disruption of the dimerization interface of the sensing domain in the dimeric heme-based oxygen sensor AfGcHK abolishes bacterial signal transduction. J. Biol. Chem. 295: 1587–1597, https://doi.org/10.1074/jbc.ra119.011574.Search in Google Scholar

Stranava, M., Martínková, M., Stiborová, M., Man, P., Kitanishi, K., Muchová, L., Vítek, L., Martínek, V., and Shimizu, T. (2014). Introduction of water into the heme distal side by Leu65 mutations of an oxygen sensor, YddV, generates verdoheme and carbon monoxide, exerting the heme oxygenase reaction. J. Inorg. Biochem. 140: 29–38, https://doi.org/10.1016/j.jinorgbio.2014.06.010.Search in Google Scholar PubMed

Stranava, M., Martínek, V., Man, P., Fojtikova, V., Kavan, D., Vaněk, O., Shimizu, T., and Martinkova, M. (2016). Structural characterization of the heme-based oxygen sensor, AfGcHK, its interactions with the cognate response regulator, and their combined mechanism of action in a bacterial two-component signaling system. Proteins 84: 1375–1389, https://doi.org/10.1002/prot.25083.Search in Google Scholar PubMed

Stranava, M., Man, P., Skálová, T., Kolenko, P., Blaha, J., Fojtikova, V., Martínek, V., Dohnálek, J., Lengalova, A., Rosůlek, M., et al.. (2017). Coordination and redox state-dependent structural changes of the heme-based oxygen sensor AfGcHK associated with intraprotein signal transduction. J. Biol. Chem. 292: 20921–20935, https://doi.org/10.1074/jbc.m117.817023.Search in Google Scholar PubMed PubMed Central

Stuehr, D.J., Misra, S., Dai, Y., and Ghosh, A. (2021). Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase. J. Biol. Chem. 296: 100336, https://doi.org/10.1016/j.jbc.2021.100336.Search in Google Scholar PubMed PubMed Central

Stuffle, E.C., Johnson, M.S., and Watts, K.J. (2021). PAS domains in bacterial signal transduction. Curr. Opin. Microbiol. 61: 8–15, https://doi.org/10.1016/j.mib.2021.01.004.Search in Google Scholar PubMed PubMed Central

Tarnawski, M., Barends, T.R.M., and Schlichting, I. (2015). Structural analysis of an oxygen-regulated diguanylate cyclase. Acta Crystallogr. D 71: 2158–2177, https://doi.org/10.1107/s139900471501545x.Search in Google Scholar

Walker, J.A., Rivera, S., and Weinert, E.E. (2017). Mechanism and role of globin-coupled sensor signalling. Adv. Microb. Physiol. 71: 133–169.10.1016/bs.ampbs.2017.05.003Search in Google Scholar PubMed PubMed Central

Wißbrock, A., Goradia, N.B., Kumar, A., George, A.A.P., Kühl, T., Bellstedt, P., Ramachandran, R., Hoffmann, P., Galler, K., Popp, J., et al.. (2019). Structural insights into heme binding to IL-36α proinflammatory cytokine. Sci. Rep. 9: 16893, https://doi.org/10.1038/s41598-019-53231-0.Search in Google Scholar PubMed PubMed Central

Yan, F., Fojtikova, V., Man, P., Stranava, M., Martínková, M., Du, Y., Huang, D., and Shimizu, T. (2015). Catalytic enhancement of the heme-based oxygen-sensing phosphodiesterase EcDOS by hydrogen sulfide is caused by changes in heme coordination structure. Biometals 28: 637–652, https://doi.org/10.1007/s10534-015-9847-7.Search in Google Scholar PubMed

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2022-0185).

Received: 2022-05-17
Accepted: 2022-09-08
Published Online: 2022-09-27
Published in Print: 2022-11-25

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Heme research – the past, the present and the future
  3. A primer on heme biosynthesis
  4. New roles for GAPDH, Hsp90, and NO in regulating heme allocation and hemeprotein function in mammals
  5. The role of host heme in bacterial infection
  6. Signal transduction mechanisms in heme-based globin-coupled oxygen sensors with a focus on a histidine kinase (AfGcHK) and a diguanylate cyclase (YddV or EcDosC)
  7. Heme delivery to heme oxygenase-2 involves glyceraldehyde-3-phosphate dehydrogenase
  8. Novel insights into heme binding to hemoglobin
  9. Extracellular hemin is a reverse use-dependent gating modifier of cardiac voltage-gated Na+ channels
  10. Assessment of the breadth of binding promiscuity of heme towards human proteins
  11. Determination of free heme in stored red blood cells with an apo-horseradish peroxidase-based assay
  12. Comparative studies of soluble and immobilized Fe(III) heme-peptide complexes as alternative heterogeneous biocatalysts
https://doi.org/10.1515/hsz-2022-0185
Keywords for this article
globin-coupled sensors; heme; heme-based sensor proteins; hemoproteins; oxygen sensors; signal transduction

Articles in the same Issue

  1. Frontmatter
  2. Heme research – the past, the present and the future
  3. A primer on heme biosynthesis
  4. New roles for GAPDH, Hsp90, and NO in regulating heme allocation and hemeprotein function in mammals
  5. The role of host heme in bacterial infection
  6. Signal transduction mechanisms in heme-based globin-coupled oxygen sensors with a focus on a histidine kinase (AfGcHK) and a diguanylate cyclase (YddV or EcDosC)
  7. Heme delivery to heme oxygenase-2 involves glyceraldehyde-3-phosphate dehydrogenase
  8. Novel insights into heme binding to hemoglobin
  9. Extracellular hemin is a reverse use-dependent gating modifier of cardiac voltage-gated Na+ channels
  10. Assessment of the breadth of binding promiscuity of heme towards human proteins
  11. Determination of free heme in stored red blood cells with an apo-horseradish peroxidase-based assay
  12. Comparative studies of soluble and immobilized Fe(III) heme-peptide complexes as alternative heterogeneous biocatalysts
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