An emerging class of novel heme-based oxygen sensors containing a globin fold binds and senses environmental O2 via a heme iron complex. Structure-function relationships of oxygen sensors containing a heme-bound globin fold are different from those containing heme-bound PAS and GAF folds. It is thus worth reconsidering from an evolutionary perspective how heme-bound proteins with a globin fold similar to that of hemoglobin and myoglobin could act as O2 sensors. Here, we summarize the molecular mechanisms of heme-based oxygen sensors containing a globin fold in an effort to shed light on the O2-sensing properties and O2-stimulated catalytic enhancement observed for these proteins.

From the Department of Biochemistry Faculty of Science Charles University Prague 128 43 Prague 2 Czech Republic

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Voet D., Voet J. G. (2011) Hemoglobin: protein function in microcosm. in Biochemistry, 4th Ed., pp. 323–358, John Wiley & Sons, New York

Antonini E., Brunori M. (1971) Hemoglobin and Myoglobin in Their Reactions with Ligands, North-Holland Publishing Co., Amsterdam

Gardner P. R., Gardner A. M., Brashear W. T., Suzuki T., Hvitved A. N., Setchell K. D. R., Olson J. S. (2006) Hemoglobins deoxygenate nitric oxide with high fidelity. J. Inorg. Biochem. 100, 542–550 PubMed

Yukl E. T., de Vries S., Moënne-Loccoz P. (2009) The millisecond intermediate in the reaction of nitric oxide with oxymyoglobin is an iron(III)-nitrato complex, not a peroxynitrite. J. Am. Chem. Soc. 131, 7234–7235 PubMed PMC

Springer B. A., Sligar S. G., Olson J. S., Phillips G. N., Jr. (1994) Mechanisms of ligand recognition in myoglobin. Chem. Rev. 94, 699–714

Shikama K. (1998) The molecular mechanism of autoxidation for myoglobin and hemoglobin: a venerable puzzle. Chem. Rev. 98, 1357–1374 PubMed

Igarashi J., Kitanishi K., Shimizu T. (2011) Emerging roles of heme as a signal and a gas-sensing site: heme-sensing and gas-sensing proteins. in Handbook of Porphyrin Science (Kadish K. M., Smith K. M., Guilard R., eds) Vol. 15, pp. 399–460, World Scientific Publishing, Hackensack, NJ

Sasakura Y., Yoshimura-Suzuki T., Kurokawa H., Shimizu T. (2006) Structure-function relationships of PubMed

Farhana A., Saini V., Kumar A., Lancaster J. R., Jr., Steyn A. J. C. (2012) Environmental heme-base sensor proteins: Implications for understanding bacterial pathogenesis. Antioxid. Redox Signal. 17, 1232–1245 PubMed PMC

Green J., Crack J. C., Thomson A. J., LeBrun N. E. (2009) Bacterial sensors of oxygen. Curr. Opin. Microbiol. 12, 145–151 PubMed

Gilles-Gonzalez M. A., Gonzalez G. (2005) Heme-based sensors: defining characteristics, recent developments, and regulatory hypotheses. J. Inorg. Biochem. 99, 1–22 PubMed

Aono S. (2012) Novel bacterial gas sensor proteins with transition metal-containing prosthetic groups as active sites. Antioxid. Redox Signal. 16, 678–686 PubMed

Uchida T., Kitagawa T. (2005) Mechanism for transduction of the ligand-binding signal in heme-based gas sensory proteins revealed by resonance Raman spectroscopy. Acc. Chem. Res. 38, 662–670 PubMed

Freitas T. A. K., Saito J. A., Hou S., Alam M. (2005) Globin-coupled sensors, protoglobins, and the last universal common ancestor. J. Inorg. Biochem. 99, 23–33 PubMed

Freitas T. A. K., Hou S., Alam M. (2003) The diversity of globin-coupled sensors. FEBS Lett. 552, 99–104 PubMed

Vinogradov S. N., Tinajero-Trejo M., Poole R. K., Hoogewijs D. (2013) Bacterial and archaeal globins–a revised perspective. Biochim. Biophys. Acta 1834, 1789–1800 PubMed

Wittenberg J. B., Bolognesi M., Wittenberg B. A., Guertin M. (2002) Truncated hemoglobins: a new family of hemoglobins widely distributed in bacteria, unicellular eukaryotes, and plants. J. Biol. Chem. 277, 871–874 PubMed

Vinogradov S. N., Moens L. (2008) Diversity of globin function: enzymatic, transport, storage, and sensing. J. Biol. Chem. 283, 8773–8777 PubMed

Pesce A., Thijs L., Nardini M., Desmet F., Sisinni L., Gourlay L., Bolli A., Coletta M., Van Doorslaer S., Wan X., Alam M., Ascenzi P., Moens L., Bolognesi M., Dewilde S. (2009) HisE11 and HisF8 provide bis-histidyl heme hexa-coordination in the globin domain of PubMed

Hou S., Larsen R. W., Boudko D., Riley C. W., Karatan E., Zimmer M., Ordal G. W., Alam M. (2000) Myoglobin-like aerotaxis transducers in Archaea and Bacteria. Nature 403, 540–544 PubMed

Hou S., Freitas T., Larsen R. W., Piatibratov M., Sivozhelezov V., Yamamoto A., Meleshkevitch E. A., Zimmer M., Ordal G. W., Alam M. (2001) Globin-coupled sensors: a class of heme-containing sensors in Archaea and Bacteria. Proc. Natl. Acad. Sci. U.S.A. 98, 9353–9358 PubMed PMC

Zhang W., Phillips G. N., Jr. (2003) Structure of the oxygen sensor in PubMed

Freitas T. A. K., Hou S., Dioum E. M., Saito J. A., Newhouse J., Gonzalez G., Gilles-Gonzalez M. A., Alam M. (2004) Ancestral hemeglobins in PubMed PMC

Zhang W., Olson J. S., Phillips G. N., Jr. (2005) Biophysical and kinetic characterization of HemAT, an aerotaxis receptor from PubMed PMC

Aono S., Kato T., Matsuki M., Nakajima H., Ohta T., Uchida T., Kitagawa T. (2002) Resonance Raman and ligand binding studies of the oxygen-sensing signal transducer protein HemAT from PubMed

Ohta T., Yoshimura H., Yoshioka S., Aono S., Kitagawa T. (2004) Oxygen-sensing mechanism of HemAT from PubMed

El-Mashtoly S. F., Kubo M., Gu Y., Sawai H., Nakashima S., Ogura T., Aono S., Kitagawa T. (2012) Site-specific protein dynamics in communication pathway from sensor to signaling domain of oxygen sensor protein, HemAT- PubMed PMC

Pinakoulaki E., Yoshimura H., Daskalakis V., Yoshioka S., Aono S., Varotsis C. (2006) Two ligand binding sites in the O PubMed PMC

Pinakoulaki E., Yoshimura H., Yoshioka S., Aono S., Varotsis C. (2006) Recognition and discrimination of gases by the oxygen-sensing signal transducer protein HemAT as revealed by FTIR. Biochemistry 45, 7763–7766 PubMed

Yoshimura H., Yoshioka S., Kobayashi K., Ohta T., Uchida T., Kubo M., Kitagawa T., Aono S. (2006) Specific hydrogen-bonding networks responsible for selective O PubMed

Casino P., Rubio V., Marina A. (2010) The mechanism of signal transduction by two-component systems. Curr. Opin. Struct. Biol. 20, 763–771 PubMed

Kitanishi K., Kobayashi K., Kawamura Y., Ishigami I., Ogura T., Nakajima K., Igarashi J., Tanaka A., Shimizu T. (2010) Important roles of Tyr43 at the putative heme distal side in the oxygen recognition and stability of the Fe(II)-O PubMed

Hengge R. (2009) Principles of c-diGMP signalling in bacteria. Nat. Rev. Microbiol. 7, 263–273 PubMed

Schirmer T., Jenal U. (2009) Structure and mechanistic determinants of c-diGMP signaling. Nat. Rev. Microbiol. 7, 724–735 PubMed

Thijs L., Vinck E., Bolli A., Trandafir F., Wan X., Hoogewijs D., Coletta M., Fago A., Weber R. E., Van Doorslaer S., Ascenzi P., Alam M., Moens L., Dewilde S. (2007) Characterization of a globin-coupled oxygen sensor with a gene-regulating function. J. Biol. Chem. 282, 37325–37340 PubMed

Wan X., Tuckerman J. R., Saito J. A., Freitas T. A. K., Newhouse J. S., Denery J. R., Galperin M. Y., Gonzalez G., Gilles-Gonzalez M. A., Alam M. (2009) Globins synthesize the second messenger bis-(3′-5′)-cyclic diguanosine monophosphate in bacteria. J. Mol. Biol. 388, 262–270 PubMed PMC

Sawai H., Yoshioka S., Uchida T., Hyodo M., Hayakawa Y., Ishimori K., Aono S. (2010) Molecular oxygen regulates the enzymatic activity of a heme-containing diguanylate cyclase (HemDGC) for the synthesis of cyclic diGMP. Biochim. Biophys. Acta 1804, 166–172 PubMed

Tuckerman J. R., Gonzalez G., Sousa E. H. S., Wan X., Saito J. A., Alam M., Gilles-Gonzalez M. A. (2009) An oxygen-sensing diguanylate cyclase and phosphodiesterase couple for c-diGMP control. Biochemistry 48, 9764–9774 PubMed

Nakajima K., Kitanishi K., Kobayashi K., Kobayashi N., Igarashi J., Shimizu T. (2012) Leu65 in the heme distal side is critical for the stability of the Fe(II)-O PubMed

Gong W., Hao B., Chan M. K. (2000) New mechanistic insights from structural studies of the oxygen-sensing domain of PubMed

Hao B., Isaza C., Arndt J., Soltis M., Chan M. K. (2002) Structure-based mechanism of O PubMed

Kurokawa H., Lee D. S., Watanabe M., Sagami I., Mikami B., Raman C. S., Shimizu T. (2004) A redox-controlled molecular switch revealed by the crystal structure of a bacterial heme PAS sensor. J. Biol. Chem. 279, 20186–20193 PubMed

Park H., Suquet C., Satterlee J. D., Kang C. (2004) Insights into signal transduction involving PAS domain oxygen-sensing heme proteins from the x-ray crystal structure of PubMed

Kitanishi K., Kobayashi K., Uchida T., Ishimori K., Igarashi J., Shimizu T. (2011) Identification and functional and spectral characterization of a globin-coupled histidine kinase from PubMed PMC

Stranzl G. R., Santelli E., Bankston L. A., La Clair C., Bobkov A., Schwarzenbacher R., Godzik A., Perego M., Grynberg M., Liddington R. C. (2011) Structural insights into inhibition of PubMed PMC

Murray J. W., Delumeau O., Lewis R. J. (2005) Structure of a nonheme globin in environmental stress signaling. Proc. Natl. Acad. Sci. U.S.A. 102, 17320–17325 PubMed PMC

Nardini M., Pesce A., Thijs L., Saito J. A., Dewilde S., Alam M., Ascenzi P., Coletta M., Ciaccio C., Moens L., Bolognesi M. (2008) Archaeal protoglobin structure indicates new ligand diffusion paths and modulation of haem-reactivity. EMBO Rep. 9, 157–163 PubMed PMC

Kumar A., Toledo J. C., Patel R. P., Lancaster J. R., Jr., Steyn A. J. C. (2007) PubMed PMC

Sousa E. H. S., Tuckerman J. R., Gonzalez G., Gilles-Gonzalez M. A. (2007) DosT and DevS are oxygen-switched kinases in PubMed PMC

Ioanoviciu A., Yukl E. T., Moënne-Loccoz P., Ortiz de Montellano P. R. (2007) DevS, a heme-containing two-component oxygen sensor PubMed PMC

Yukl E. T., Ioanoviciu A., Nakano M. M., Ortiz de Montellano P. R., Moënne-Loccoz P. (2008) A distal tyrosine residue is required for ligand discrimination in DevS from PubMed PMC

Ioanoviciu A., Meharenna Y. T., Poulos T. L., Ortiz de Montellano P. R. (2009) DevS oxy complex stability identified this heme protein as a gas sensor in PubMed PMC

Cho H. Y., Cho H. J., Kim Y. M., Oh J. I., Kang B. S. (2009) Structural insight into the heme-based redox sensing by DosS from PubMed PMC

Vos M. H., Bouzhir-Sima L., Lambry J.-C., Luo H., Eaton-Rye J. J., Ioanoviciu A., Ortiz de Montellano P. R., Liebl U. (2012) Ultrafast ligand dynamics in the heme-based GAF sensor domains of the histidine kinases DosS and DosT from PubMed PMC

Podust L. M., Ioanoviciu A., Ortiz de Montellano P. R. (2008) 2.3 Å x-ray structure of the heme-bound GAF domain of sensory histidine kinase DosT of PubMed PMC

Gilles-Gonzalez M. A., Ditta G. S., Helinski D. R. (1991) A haemoprotein with kinase activity encoded by the oxygen sensor of PubMed

Gong W., Hao B., Mansy S. S., Gonzalez G., Gilles-Gonzalez M. A., Chan M. K. (1998) Structure of a biological oxygen sensor: a new mechanism for heme-driven signal transduction. Proc. Natl. Acad. Sci. U.S.A. 95, 15177–15182 PubMed PMC

Gilles-Gonzalez M. A., Caceres A. I., Sousa E. H. S., Tomchick D. R., Brautigam C., Gonzalez C., Machius M. (2006) A proximal arginine R206 participates in switching of the PubMed

Miyatake H., Mukai M., Park S. Y., Adachi S., Tamura K., Nakamura H., Nakamura K., Tsuchiya T., Iizuka T., Shiro Y. (2000) Sensory mechanism of oxygen sensor FixL from PubMed

Yamada S., Sugimoto H., Kobayashi M., Ohno A., Nakamura H., Shiro S. (2009) Structure of PAS-linked histidine kinase and the response regulator complex. Structure 17, 1333–1344 PubMed

Nakamura H., Kumita H., Imai K., Iizuka T., Shiro Y. (2004) ADP reduces the oxygen-binding affinity of a sensory histidine kinase, FixL: the possibility of an enhanced reciprocating kinase reaction. Proc. Natl. Acad. Sci. U.S.A. 101, 2742–2746 PubMed PMC

Nuernberger P., Lee K. F., Bonvalet A., Bouzhir-Sima L., Lambry J.-C., Liebl U., Joffre M., Vos M. H. (2011) Strong ligand-protein interactions revealed by ultrafast infrared spectroscopy of CO in the heme pocket of the oxygen sensor FixL. J. Am. Chem. Soc. 133, 17110–17113 PubMed

Gonzalez G., Gilles-Gonzalez M. A., Rybak-Akimova E. V., Buchalova M., Busch D. H. (1998) Mechanisms of autooxidation of the oxygen sensor FixL and PubMed

Delgado-Nixon V. M., Gonzalez G., Gilles-Gonzalez M. A. (2000) Dos, a heme-binding PAS protein from PubMed

Sasakura Y., Hirata S., Sugiyama S., Suzuki S., Taguchi S., Watanabe M., Matsui T., Sagami I., Shimizu T. (2002) Characterization of a direct oxygen sensor heme protein from PubMed

Taguchi S., Matsui T., Igarashi J., Sasakura Y., Araki Y., Ito O., Sugiyama S., Sagami I., Shimizu T. (2004) Binding of oxygen and carbon monoxide to a heme-regulated phosphodiesterase from PubMed

Tanaka A., Takahashi H., Shimizu T. (2007) Critical role of the heme axial ligand, Met PubMed

Ishitsuka Y., Araki Y., Tanaka A., Igarashi J., Ito O., Shimizu T. (2008) Arg97 at the heme distal side of the isolated heme-bound PAS domain of a heme-based oxygen sensor from PubMed

Kobayashi K., Tanaka A., Takahashi H., Igarashi J., Ishitsuka Y., Yokota N., Shimizu T. (2010) Catalysis and oxygen binding of PubMed

Yamashita T., Bouzhir-Sima L., Lambry J.-C., Liebl U., Vos M. H. (2008) Ligand dynamics and early signaling events in the heme domain of the sensor protein Dos from PubMed

Lechauve C., Bouzhir-Sima L., Yamashita T., Marden M. C., Vos M. H., Liebl U., Kiger L. (2009) Heme ligand binding properties and intradimer interactions in the full-length sensor protein Dos from PubMed PMC

Shimizu T. (2013) The heme-based oxygen-sensor phosphodiesterase PubMed PMC

Yang J., Kloek A. P., Goldberg D. E., Mathews F. S. (1995) The structure of PubMed PMC

Dunham C. M., Dioum E. M., Tuckerman J. R., Gonzalez G., Scott W. G., Gilles-Gonzalez M. A. (2003) A distal arginine in oxygen-sensing heme-PAS domain is essential to ligand binding, signal transduction, and structure. Biochemistry 42, 7701–7708 PubMed

Derbyshire E. R., Winter M. B., Ibrahim M., Deng S., Spiro T. G., Marletta M. A. (2011) Probing domain interactions in soluble guanylate cyclase. Biochemistry 50, 4281–4290 PubMed PMC

Derbyshire E. R., Marletta M. A. (2012) Structure and regulation of soluble guanylate cyclase. Annu. Rev. Biochem. 81, 533–559 PubMed

Yazawa S., Tsuchiya H., Hori H., Makino R. (2006) Functional characterization of two nucleotide-binding sites in soluble guanylate cyclase. J. Biol. Chem. 281, 21763–21770 PubMed

Makino R., Park S. Y., Obayashi E., Iizuka T., Hori H., Shiro Y. (2011) Oxygen binding and redox properties of the heme in soluble guanylate cyclase: implications for the mechanism of ligand discrimination. J. Biol. Chem. 286, 15678–15687 PubMed PMC

Mujoo K., Sharin V. G., Bryan N. S., Krumenacker J. S., Sloan C., Parveen S., Nikonoff L. E., Kots A. Y., Murad F. (2008) Role of nitric oxide signaling components in differentiation of embryonic stem cells into myocardial cells. Proc. Natl. Acad. Sci. U.S.A. 105, 18924–18929 PubMed PMC

Winter M. B., Herzik M. A., Jr., Kuriyan J., Marletta M. A. (2011) Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain. Proc. Natl. Acad. Sci. U.S.A. 108, E881–E889 PubMed PMC

Plate L., Marletta M. A. (2012) Nitric oxide modulates bacterial biofilm formation through a multicomponent cyclic-diGMP signaling network. Mol. Cell 46, 449–460 PubMed PMC

Liu N., Xu Y., Hossain S., Huang N., Coursolle D., Gralnick J. A., Boon E. M. (2012) Nitric oxide regulation of cyclic diGMP synthesis and hydrolysis in PubMed

Muralidharan S., Boon E. M. (2012) Heme flattering is sufficient for signal transduction in the H-NOX family. J. Am. Chem. Soc. 134, 2044–2046 PubMed

Roberts G. P., Youn H., Kerby R. L. (2004) CO-sensing mechanism. Microbiol. Mol. Biol. Rev. 68, 453–473 PubMed PMC

Youn H., Kerby R. L., Roberts G. P. (2004) Changing the ligand specificity of CooA, a highly specific heme-based CO sensor. J. Biol. Chem. 279, 45744–45752 PubMed

Benabbas A., Karunakaran V., Youn H., Poulos T. L., Champion P. M. (2012) Effect of DNA binding on geminate CO recombination kinetics in the CO-sensing transcriptional factor, CooA. J. Biol. Chem. 287, 21729–21740 PubMed PMC

Lee A. J., Clark R. W., Youn H., Ponter S., Burstyn J. N. (2009) Guanidine hydrochloride-induced unfolding of the three heme coordination states of the CO-sensing transcription factor, CooA. Biochemistry 48, 6585–6597 PubMed PMC

Clark R. W., Youn H., Lee A. J., Roberts G. P., Burstyn J. N. (2007) DNA binding by an imidazole-sensing CooA variant is dependent on the heme redox state. J. Biol. Inorg. Chem. 12, 139–146 PubMed

Kubo M., Inagaki S., Yoshioka S., Uchida T., Mizutani Y., Aono S., Kitagawa T. (2006) Evidence for displacements of the C-helix by CO ligation and DNA binding to CooA revealed by UV resonance Raman spectroscopy. J. Biol. Chem. 281, 11271–11278 PubMed

Ibrahim M., Kerby R. L., Puranik M., Wasbotten I. H., Youn H., Roberts G. P., Spiro T. G. (2006) Heme displacement mechanism of CooA activation: mutational and Raman spectroscopic evidence. J. Biol. Chem. 281, 29165–29173 PubMed PMC

Komori H., Inagaki S., Yoshioka S., Aono S., Higuchi Y. (2007) Crystal structure of CO-sensing transcription activator CooA bound to exogenous ligand imidazole. J. Mol. Biol. 367, 864–871 PubMed

Tsai A. L., Berka V., Martin E., Olson J. S. (2012) A “sliding scale rule” for selectivity among NO, CO, and O PubMed PMC

Tsai A. L., Martin E., Berka V., Olson J. S. (2012) How do heme-protein sensors exclude oxygen? Lessons learned from cytochrome PubMed PMC

Tanaka A., Shimizu T. (2008) Ligand binding to the Fe(III)-protoporphyrin IX complex of phosphodiesterase from PubMed

Chang A. L., Tuckerman J. R., Gonzalez G., Mayer R., Weinhouse H., Volman G., Amikam D., Benziman M., Gilles-Gonzalez M. A. (2001) Phosphodiesterase A1, a regulator of cellulose synthesis in PubMed

Watts K. J., Taylor B. L., Johnson M. S. (2011) PAS/poly-HAMP signalling in Aer-2, a soluble haem-based sensor. Mol. Microbiol. 79, 686–699 PubMed PMC

Sawai H., Sugimoto H., Shiro Y., Ishikawa H., Mizutani Y., Aono S. (2012) Structural basis for oxygen sensing and signal transduction of the heme-based sensor protein Aer2 from PubMed

Vojtěchovský J., Chu K., Berendzen J., Sweet R. M., Schlichting I. (1999) Crystal structures of myoglobin-ligand complexes at near-atomic resolution. Biophys. J. 77, 2153–2174 PubMed PMC

Pesce A., Nardini M., Dewilde S., Capece L., Martí M. A., Congia S., Salter M. D., Blouin G. C., Estrin D. A., Ascenzi P., Moens L., Bolognesi M., Olson J. S. (2011) Ligand migration in the apolar tunnel of PubMed PMC

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