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• W2897024970 abstract "In order to proliferate and mount an infection, many bacterial pathogens need to acquire iron from their host. The most abundant iron source in the body is the oxygen transporter hemoglobin (Hb). Streptococcus pyogenes, a potentially lethal human pathogen, uses the Shr protein to capture Hb on the cell surface. Shr is an important virulence factor, yet the mechanism by which it captures Hb and acquires its heme is not well-understood. Here, we show using NMR and biochemical methods that Shr binds Hb using two related modules that were previously defined as domains of unknown function (DUF1533). These hemoglobin-interacting domains (HIDs), called HID1 and HID2, are autonomously folded and independently bind Hb. The 1.5 Å resolution crystal structure of HID2 revealed that it is a structurally unique Hb-binding domain. Mutagenesis studies revealed a conserved tyrosine in both HIDs that is essential for Hb binding. Our biochemical studies indicate that HID2 binds Hb with higher affinity than HID1 and that the Hb tetramer is engaged by two Shr receptors. NMR studies reveal the presence of a third autonomously folded domain between HID2 and a heme-binding NEAT1 domain, suggesting that this linker domain may position NEAT1 near Hb for heme capture. In order to proliferate and mount an infection, many bacterial pathogens need to acquire iron from their host. The most abundant iron source in the body is the oxygen transporter hemoglobin (Hb). Streptococcus pyogenes, a potentially lethal human pathogen, uses the Shr protein to capture Hb on the cell surface. Shr is an important virulence factor, yet the mechanism by which it captures Hb and acquires its heme is not well-understood. Here, we show using NMR and biochemical methods that Shr binds Hb using two related modules that were previously defined as domains of unknown function (DUF1533). These hemoglobin-interacting domains (HIDs), called HID1 and HID2, are autonomously folded and independently bind Hb. The 1.5 Å resolution crystal structure of HID2 revealed that it is a structurally unique Hb-binding domain. Mutagenesis studies revealed a conserved tyrosine in both HIDs that is essential for Hb binding. Our biochemical studies indicate that HID2 binds Hb with higher affinity than HID1 and that the Hb tetramer is engaged by two Shr receptors. NMR studies reveal the presence of a third autonomously folded domain between HID2 and a heme-binding NEAT1 domain, suggesting that this linker domain may position NEAT1 near Hb for heme capture. Streptococcus pyogenes (Group A Streptococcus) each year causes an estimated 700 million infections worldwide (1Zhu L. Charbonneau A.R.L. Waller A.S. Olsen R.J. Beres S.B. Musser J.M. Novel genes required for the fitness of Streptococcus pyogenes in human saliva.mSphere. 2017; 2 (29104937): e00460-17Crossref PubMed Google Scholar). Although most of these infections lead to nonlife-threatening acute pharyngitis, many are lethal and cause ∼500,000 deaths annually (2Carapetis J.R. Steer A.C. Mulholland E.K. Weber M. The global burden of group A streptococcal diseases.Lancet Infect. Dis. 2005; 5 (16253886): 685-694Abstract Full Text Full Text PDF PubMed Scopus (1960) Google Scholar). These more severe and invasive infections have a high mortality rate (∼30%) and include necrotizing fasciitis and streptococcal toxic shock syndrome (3Stevens D.L. Streptococcal toxic-shock syndrome: spectrum of disease, pathogenesis, and new concepts in treatment.Emerg. Infect. Dis. 1995; 1 (8903167): 69-7810.3201/eid0103.950301Crossref PubMed Scopus (392) Google Scholar, 4Tsatsaronis J.A. Walker M.J. Sanderson-Smith M.L. Host responses to group A Streptococcus: cell death and inflammation.PLoS Pathog. 2014; 10 (25165887)e1004266Crossref PubMed Scopus (38) Google Scholar). Infections caused by this deadly microbe are presently among the top 10 causes of death from an infectious disease worldwide (5Ralph A.P. Carapetis J.R. Group A streptococcal diseases and their global burden.Curr. Top. Microbiol. Immunol. 2013; 368 (23242849): 1-27PubMed Google Scholar). S. pyogenes and other pathogenic bacteria require iron to proliferate, as it is a versatile metal that functions as a key biocatalyst and electron carrier in enzymes that mediate metabolism (6Ge R. Sun X. Iron acquisition and regulation systems in Streptococcus species.Metallomics. 2014; 6 (24663493): 996-100310.1039/c4mt00011kCrossref PubMed Scopus (23) Google Scholar). During infections, iron is frequently foraged from human hemoglobin (Hb), 3The abbreviations used are: HbhemoglobinShrstreptococcal hemoprotein receptorHIDhemoglobin interacting domainHSQCheteronuclear single quantum coherenceSEC-MALSsize-exclusion chromatography with inline multiangle light scatteringITCisothermal titration calorimetryAUCanalytical ultracentrifugationCTRC-terminal regionNTRN-terminal regionPDBProtein Data BankCVcolumn volumer.m.s.d.root mean square deviation. which contains ∼75–80% of the body’s total iron content in the form of heme (iron–protoporphyrin IX). Recent studies have shown that S. pyogenes uses an array of surface and membrane-associated proteins to acquire Hb’s heme. Understanding how these proteins function at a molecular level is of fundamental importance and could facilitate the discovery of new anti-infective agents that work by limiting microbial access to iron. hemoglobin streptococcal hemoprotein receptor hemoglobin interacting domain heteronuclear single quantum coherence size-exclusion chromatography with inline multiangle light scattering isothermal titration calorimetry analytical ultracentrifugation C-terminal region N-terminal region Protein Data Bank column volume root mean square deviation. Surface and membrane-associated proteins are used by S. pyogenes to capture heme. The streptococcal hemoprotein receptor (Shr) is displayed on the bacterium’s surface, where it binds to Hb and acquires the oxidized form of heme (called hemin) (7Bates C.S. Montañez G.E. Woods C.R. Vincent R.M. Eichenbaum Z. Identification and characterization of a Streptococcus pyogenes operon involved in binding of hemoproteins and acquisition of iron.Infect. Immun. 2003; 71 (12595414): 1042-105510.1128/IAI.71.3.1042-1055.2003Crossref PubMed Scopus (118) Google Scholar8Ouattara M. Cunha E.B. Li X. Huang Y.S. Dixon D. Eichenbaum Z. Shr of group A Streptococcus is a new type of composite NEAT protein involved in sequestering haem from methaemoglobin.Mol. Microbiol. 2010; 78 (20807204): 739-75610.1111/j.1365-2958.2010.07367.xCrossref PubMed Scopus (53) Google Scholar, 9Lu C. Xie G. Liu M. Zhu H. Lei B. Direct heme transfer reactions in the group A Streptococcus heme acquisition pathway.PLoS ONE. 2012; 7 (22649539)e3755610.1371/journal.pone.0037556Crossref PubMed Scopus (16) Google Scholar, 10Fisher M. Huang Y.S. Li X. McIver K.S. Toukoki C. Eichenbaum Z. Shr is a broad-spectrum surface receptor that contributes to adherence and virulence in group A Streptococcus.Infect. Immun. 2008; 76 (18710861): 5006-501510.1128/IAI.00300-08Crossref PubMed Scopus (68) Google Scholar11Hoshino M. Nakakido M. Nagatoishi S. Aikawa C. Nakagawa I. Tsumoto K. Biophysical characterization of the interaction between heme and proteins responsible for heme transfer in Streptococcus pyogenes.Biochem. Biophys. Res. Commun. 2017; 493 (28919415): 1109-111410.1016/j.bbrc.2017.09.055Crossref PubMed Scopus (4) Google Scholar). The Shr Hb receptor is an important virulence factor, as Δshr mutant strains of S. pyogenes exhibit reduced growth in human blood and attenuated virulence in murine and zebrafish models of infection (10Fisher M. Huang Y.S. Li X. McIver K.S. Toukoki C. Eichenbaum Z. Shr is a broad-spectrum surface receptor that contributes to adherence and virulence in group A Streptococcus.Infect. Immun. 2008; 76 (18710861): 5006-501510.1128/IAI.00300-08Crossref PubMed Scopus (68) Google Scholar, 12Dahesh S. Nizet V. Cole J.N. Study of streptococcal hemoprotein receptor (Shr) in iron acquisition and virulence of M1T1 group A Streptococcus.Virulence. 2012; 3 (23076332): 566-57510.4161/viru.21933Crossref PubMed Scopus (29) Google Scholar). In vitro, Shr transfers hemin directly to Shp, a cell wall–associated hemoprotein that uses a bis-methionine ligation mechanism to interact with hemin (13Aranda 4th, R. Worley C.E. Liu M. Bitto E. Cates M.S. Olson J.S. Lei B. Phillips Jr., G.N. Bis-methionyl coordination in the crystal structure of the heme-binding domain of the streptococcal cell surface protein Shp.J. Mol. Biol. 2007; 374 (17920629): 374-38310.1016/j.jmb.2007.08.058Crossref PubMed Scopus (44) Google Scholar, 14Lei B. Smoot L.M. Menning H.M. Voyich J.M. Kala S.V. Deleo F.R. Reid S.D. Musser J.M. Identification and characterization of a novel heme-associated cell surface protein made by Streptococcus pyogenes.Infect. Immun. 2002; 70 (12117961): 4494-450010.1128/IAI.70.8.4494-4500.2002Crossref PubMed Scopus (88) Google Scholar15Vicente J.J. Galardi-Castilla M. Escalante R. Sastre L. The surface protein Shr of Streptococcus pyogenes binds heme and transfers it to the streptococcal heme-binding protein Shp.BMC Microbiol. 2008; 8 (18173832): 1510.1186/1471-2180-8-1Crossref PubMed Scopus (64) Google Scholar). Shp then passes hemin to HtsA/SiaA, the lipoprotein component of the ABC transporter HtsABC/SiaABC (16Liu M. Lei B. Heme transfer from streptococcal cell surface protein Shp to HtsA of transporter HtsABC.Infect. Immun. 2005; 73 (16041024): 5086-509210.1128/IAI.73.8.5086-5092.2005Crossref PubMed Scopus (57) Google Scholar). A binary Shp–HtsA complex mediates this transfer step, in which the methionine axial ligands in Shp are displaced by methionine and histidine axial ligands within HtsA (17Ran Y. Malmirchegini G.R. Clubb R.T. Lei B. Axial ligand replacement mechanism in heme transfer from streptococcal heme-binding protein shp to HtsA of the HtsABC transporter.Biochemistry. 2013; 52 (23980583): 6537-654710.1021/bi400965uCrossref PubMed Scopus (11) Google Scholar18Nygaard T.K. Blouin G.C. Liu M. Fukumura M. Olson J.S. Fabian M. Dooley D.M. Lei B. The mechanism of direct heme transfer from the streptococcal cell surface protein Shp to HtsA of the HtsABC transporter.J. Biol. Chem. 2006; 281 (16717094): 20761-2077110.1074/jbc.M601832200Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 19Ran Y. Zhu H. Liu M. Fabian M. Olson J.S. Aranda 4th, R. Phillips Jr., G.N. Dooley D.M. Lei B. Bis-methionine ligation to heme iron in the streptococcal cell surface protein Shp facilitates rapid hemin transfer to HtsA of the HtsABC transporter.J. Biol. Chem. 2007; 282 (17699155): 31380-3138810.1074/jbc.M705967200Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 20Lei B. Benfang Lei's research on heme acquisition in Gram-positive pathogens and bacterial pathogenesis.World J. Biol. Chem. 2010; 1 (21537486): 286-29010.4331/wjbc.v1.i9.286Crossref PubMed Google Scholar21Ran Y. Liu M. Zhu H. Nygaard T.K. Brown D.E. Fabian M. Dooley D.M. Lei B. Spectroscopic identification of heme axial ligands in HtsA that are involved in heme acquisition by Streptococcus pyogenes.Biochemistry. 2010; 49 (20180543): 2834-284210.1021/bi901987hCrossref PubMed Scopus (24) Google Scholar). This process occurs very rapidly, >100,000 times faster than the rate at which Shp spontaneously releases hemin into the solvent. Hemin is then presumably transported across the membrane into the bacterial cytoplasm where it is degraded by a yet to be identified oxygenase(s) that releases hemin’s iron for use by the microbe (6Ge R. Sun X. Iron acquisition and regulation systems in Streptococcus species.Metallomics. 2014; 6 (24663493): 996-100310.1039/c4mt00011kCrossref PubMed Scopus (23) Google Scholar). Although hemin transfer from Shp to HtsA/SiaA has been extensively studied by Lei and co-workers (20Lei B. Benfang Lei's research on heme acquisition in Gram-positive pathogens and bacterial pathogenesis.World J. Biol. Chem. 2010; 1 (21537486): 286-29010.4331/wjbc.v1.i9.286Crossref PubMed Google Scholar), the first step in the pathway, the extraction of hemin from human Hb by Shr, is less well-understood and the focus of this study. Many Gram-positive bacterial pathogens display Hb receptors that contain near–iron transport (NEAT) domains (22Andrade M. Ciccarelli F.D. Perez-Iratxeta C. Bork P. NEAT: a domain duplicated in genes near the components of a putative Fe3+ siderophore transporter from Gram-positive pathogenic bacteria.Genome Biol. 2002; 3 (12225586)RESEARCH0047Crossref PubMed Google Scholar, 23Sheldon J.R. Heinrichs D.E. Recent developments in understanding the iron acquisition strategies of Gram positive pathogens.FEMS Microbiol. Rev. 2015; 39 (25862688): 592-63010.1093/femsre/fuv009Crossref PubMed Scopus (161) Google Scholar). NEAT domains have been shown to bind Hb, hemin, and in many instances are able to rapidly transfer hemin among one another (24Pilpa R.M. Fadeev E.A. Villareal V.A. Wong M.L. Phillips M. Clubb R.T. Solution structure of the NEAT (NEAr Transporter) domain from IsdH/HarA: the human hemoglobin receptor in Staphylococcus aureus.J. Mol. Biol. 2006; 360 (16762363): 435-44710.1016/j.jmb.2006.05.019Crossref PubMed Scopus (79) Google Scholar25Dryla A. Hoffmann B. Gelbmann D. Giefing C. Hanner M. Meinke A. Anderson A.S. Koppensteiner W. Konrat R. von Gabain A. Nagy E. High-affinity binding of the staphylococcal HarA protein to haptoglobin and hemoglobin involves a domain with an antiparallel eight-stranded β-barrel fold.J. Bacteriol. 2007; 189 (17041047): 254-26410.1128/JB.01366-06Crossref PubMed Scopus (58) Google Scholar, 26Watanabe M. Tanaka Y. Suenaga A. Kuroda M. Yao M. Watanabe N. Arisaka F. Ohta T. Tanaka I. Tsumoto K. Structural basis for multimeric heme complexation through a specific protein-heme interaction: the case of the third NEAT domain of IsdH from Staphylococcus aureus.J. Biol. Chem. 2008; 283 (18667422): 28649-2865910.1074/jbc.M803383200Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 27Liu M. Tanaka W.N. Zhu H. Xie G. Dooley D.M. Lei B. Direct hemin transfer from IsdA to IsdC in the iron-regulated surface determinant (Isd) heme acquisition system of Staphylococcus aureus.J. Biol. Chem. 2008; 283 (18184657): 6668-667610.1074/jbc.M708372200Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 28Fabian M. Solomaha E. Olson J.S. Maresso A.W. Heme transfer to the bacterial cell envelope occurs via a secreted hemophore in the Gram-positive pathogen Bacillus anthracis.J. Biol. Chem. 2009; 284 (19759022): 32138-3214610.1074/jbc.M109.040915Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 29Pilpa R.M. Robson S.A. Villareal V.A. Wong M.L. Phillips M. Clubb R.T. Functionally distinct NEAT (NEAr transporter) domains within the Staphylococcus aureus IsdH/HarA protein extract heme from methemoglobin.J. Biol. Chem. 2009; 284 (18984582): 1166-117610.1074/jbc.M806007200Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 30Villareal V.A. Spirig T. Robson S.A. Liu M. Lei B. Clubb R.T. Transient weak protein-protein complexes transfer heme across the cell wall of Staphylococcus aureus.J. Am. Chem. Soc. 2011; 133 (21834592): 14176-1417910.1021/ja203805bCrossref PubMed Scopus (52) Google Scholar, 31Gaudin C.F.M. Grigg J.C. Arrieta A.L. Murphy M.E. 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Solution structure and molecular determinants of hemoglobin binding of the first NEAT domain of IsdB in Staphylococcus aureus.Biochemistry. 2014; 53 (24871270): 3922-393310.1021/bi5005188Crossref PubMed Scopus (25) Google Scholar35Moriwaki Y. Terada T. Tsumoto K. Shimizu K. Rapid heme transfer reactions between NEAr transporter domains of staphylococcus aureus: a theoretical study using QM/MM and MD simulations.PLoS ONE. 2015; 10 (26658942)e014512510.1371/journal.pone.0145125Crossref PubMed Scopus (8) Google Scholar). Hemin acquisition by Staphylococcus aureus has been studied extensively. This microbe uses an array of iron-regulated surface determinant (Isd) proteins that each contain one or more NEAT domains (24Pilpa R.M. Fadeev E.A. Villareal V.A. Wong M.L. Phillips M. Clubb R.T. Solution structure of the NEAT (NEAr Transporter) domain from IsdH/HarA: the human hemoglobin receptor in Staphylococcus aureus.J. Mol. 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Robson S.A. Fadeev E.A. Clubb R.T. The IsdC protein from Staphylococcus aureus uses a flexible binding pocket to capture heme.J. Biol. Chem. 2008; 283 (18715872): 31591-3160010.1074/jbc.M801126200Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 39Sharp K.H. Schneider S. Cockayne A. Paoli M. Crystal structure of the heme-IsdC complex, the central conduit of the Isd iron/heme uptake system in Staphylococcus aureus.J. Biol. Chem. 2007; 282 (17287214): 10625-1063110.1074/jbc.M700234200Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar40Pluym M. Muryoi N. Heinrichs D.E. Stillman M.J. Heme binding in the NEAT domains of IsdA and IsdC of Staphylococcus aureus.J. Inorg. Biochem. 2008; 102 (18194816): 480-48810.1016/j.jinorgbio.2007.11.011Crossref PubMed Scopus (43) Google Scholar). Hb is captured on the cell surface by the closely related IsdB and IsdH proteins (41Pishchany G. Dickey S.E. Skaar E.P. Subcellular localization of the Staphylococcus aureus heme iron transport components IsdA and IsdB.Infect. Immun. 2009; 77 (19398548): 2624-263410.1128/IAI.01531-08Crossref PubMed Scopus (57) Google Scholar). Our studies have shown that IsdH captures and extracts hemin from Hb using a conserved tri-domain unit that contains two NEAT domains, called N2 and N3, that are separated by a helical linker domain (42Spirig T. Malmirchegini G.R. Zhang J. Robson S.A. Sjodt M. Liu M. Krishna Kumar K. Dickson C.F. Gell D.A. Lei B. Loo J.A. Clubb R.T. Staphylococcus aureus uses a novel multidomain receptor to break apart human hemoglobin and steal its heme.J. Biol. Chem. 2013; 288 (23132864): 1065-107810.1074/jbc.M112.419119Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). As compared with the rate of hemin released into the solvent by Hb, binding of the tri-domain unit accelerates hemin release 13,400-fold (43Sjodt M. Macdonald R. Marshall J.D. Clayton J. Olson J.S. Phillips M. Gell D.A. Wereszczynski J. Clubb R.T. Energetics underlying hemin extraction from human hemoglobin by Staphylococcus aureus.J. Biol. Chem. 2018; 293 (29540481): 6942-695710.1074/jbc.RA117.000803Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Atomic structures of IsdH–Hb complexes reveal that its N2 and N3 NEAT domains adopt related β-sandwich structures that are decorated by short helices, whereas the intervening linker domain adopts a three-helix bundle (44Dickson C.F. Kumar K.K. Jacques D.A. Malmirchegini G.R. Spirig T. Mackay J.P. Clubb R.T. Guss J.M. Gell D.A. Structure of the hemoglobin-IsdH complex reveals the molecular basis of iron capture by Staphylococcus aureus.J. Biol. Chem. 2014; 289 (24425866): 6728-673810.1074/jbc.M113.545566Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 45Dickson C.F. Jacques D.A. Clubb R.T. Guss J.M. Gell D.A. The structure of haemoglobin bound to the haemoglobin receptor IsdH from Staphylococcus aureus shows disruption of the native α-globin haem pocket.Acta Crystallogr. D Biol. Crystallogr. 2015; 71 (26057669): 1295-130610.1107/S1399004715005817Crossref PubMed Scopus (18) Google Scholar). The N2 domain engages Hb’s A-helix with high affinity, enabling the helical and N3 domains to distort Hb’s F-helix, thereby promoting hemin transfer to IsdH’s N3 domain (43Sjodt M. Macdonald R. Marshall J.D. Clayton J. Olson J.S. Phillips M. Gell D.A. Wereszczynski J. Clubb R.T. Energetics underlying hemin extraction from human hemoglobin by Staphylococcus aureus.J. Biol. Chem. 2018; 293 (29540481): 6942-695710.1074/jbc.RA117.000803Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 45Dickson C.F. Jacques D.A. Clubb R.T. Guss J.M. Gell D.A. The structure of haemoglobin bound to the haemoglobin receptor IsdH from Staphylococcus aureus shows disruption of the native α-globin haem pocket.Acta Crystallogr. D Biol. Crystallogr. 2015; 71 (26057669): 1295-130610.1107/S1399004715005817Crossref PubMed Scopus (18) Google Scholar, 46Sjodt M. Macdonald R. Spirig T. Chan A.H. Dickson C.F. Fabian M. Olson J.S. Gell D.A. Clubb R.T. The PRE-derived NMR model of the 38.8-kDa tri-domain IsdH protein from Staphylococcus aureus suggests that it adaptively recognizes human hemoglobin.J. Mol. Biol. 2016; 428 (25687963): 1107-112910.1016/j.jmb.2015.02.008Crossref PubMed Scopus (18) Google Scholar). IsdB shares significant primary sequence homology with IsdH and also contains a tri-domain unit that captures hemin from Hb through a similar mechanism (31Gaudin C.F.M. Grigg J.C. Arrieta A.L. Murphy M.E. Unique heme-iron coordination by the hemoglobin receptor IsdB of Staphylococcus aureus.Biochemistry. 2011; 50 (21574663): 5443-545210.1021/bi200369pCrossref PubMed Scopus (71) Google Scholar, 34Fonner B.A. Tripet B.P. Eilers B.J. Stanisich J. Sullivan-Springhetti R.K. Moore R. Liu M. Lei B. Copié V. Solution structure and molecular determinants of hemoglobin binding of the first NEAT domain of IsdB in Staphylococcus aureus.Biochemistry. 2014; 53 (24871270): 3922-393310.1021/bi5005188Crossref PubMed Scopus (25) Google Scholar, 42Spirig T. Malmirchegini G.R. Zhang J. Robson S.A. Sjodt M. Liu M. Krishna Kumar K. Dickson C.F. Gell D.A. Lei B. Loo J.A. Clubb R.T. Staphylococcus aureus uses a novel multidomain receptor to break apart human hemoglobin and steal its heme.J. Biol. Chem. 2013; 288 (23132864): 1065-107810.1074/jbc.M112.419119Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 47Bowden C.F. Verstraete M.M. Eltis L.D. Murphy M.E. 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Structure-function analyses reveal key features in Staphylococcus aureus IsdB-associated unfolding of the heme-binding pocket of human hemoglobin.J. Biol. Chem. 2018; 293 (29109153): 177-19010.1074/jbc.M117.806562Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Other Gram-positive pathogens use NEAT domains to bind hemin and/or Hb, and include among others Listeria monocytogenes, Bacillus anthracis, Bacillus cereus, and S. pyogenes (23Sheldon J.R. Heinrichs D.E. Recent developments in understanding the iron acquisition strategies of Gram positive pathogens.FEMS Microbiol. Rev. 2015; 39 (25862688): 592-63010.1093/femsre/fuv009Crossref PubMed Scopus (161) Google Scholar). However, the mechanisms used by these domains to capture hemin from Hb may be distinct from that in IsdH and IsdB, because in some instances a single NEAT domain has been proposed to bind to both Hb and heme (51Malmirchegini G.R. Sjodt M. Shnitkind S. Sawaya M.R. Rosinski J. Newton S.M. Klebba P.E. Clubb R.T. Novel mechanism of hemin capture by Hbp2, the hemoglobin-binding hemophore from Listeria monocytogenes.J. Biol. Chem. 2014; 289 (25315777): 34886-3489910.1074/jbc.M114.583013Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar52Maresso A.W. Garufi G. Schneewind O. Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin.PLoS Pathog. 2008; 4 (18725935)e100013210.1371/journal.ppat.1000132Crossref PubMed Scopus (103) Google Scholar, 53Honsa E.S. Fabian M. Cardenas A.M. Olson J.S. Maresso A.W. The five near-iron transporter (NEAT) domain anthrax hemophore, IsdX2, scavenges heme from hemoglobin and transfers heme to the surface protein IsdC.J. Biol. Chem. 2011; 286 (21808055): 33652-3366010.1074/jbc.M111.241687Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar54Balderas M.A. Nobles C.L. Honsa E.S. Alicki E.R. Maresso A.W. Hal is a Bacillus anthracis heme acquisition protein.J. Bacteriol. 2012; 194 (22865843): 5513-552110.1128/JB.00685-12Crossref PubMed Scopus (31) Google Scholar). Notable examples are IsdX1, IsdX2, and Hal in which single NEAT domains from these proteins have been reported to bind Hb and extract hemin from Hb (52Maresso A.W. Garufi G. Schneewind O. Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin.PLoS Pathog. 2008; 4 (18725935)e100013210.1371/journal.ppat.1000132Crossref PubMed Scopus (103) Google Scholar, 53Honsa E.S. Fabian M. Cardenas A.M. Olson J.S. Maresso A.W. The five near-iron transporter (NEAT) domain anthrax hemophore, IsdX2, scavenges heme from hemoglobin and transfers heme to the surface protein IsdC.J. Biol. Chem. 2011; 286 (21808055): 33652-3366010.1074/jbc.M111.241687Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar54Balderas M.A. Nobles C.L. Honsa E.S. Alicki E.R. Maresso A.W. Hal is a Bacillus anthracis heme acquisition protein.J. Bacteriol. 2012; 194 (22865843): 5513-552110.1128/JB.00685-12Crossref PubMed Scopus (31) Google Scholar). However, complexes of these NEAT domains bound to Hb have not been visualized at atomic resolution. Unlike other Hb receptors in Gram-positive bacteria, the S. pyogenes Shr protein does not use NEAT domains to engage Hb. Instead, it binds Hb via an N-terminal region (NTR) that is predicted to contain two domains of unknown function, called DUF1533 domains (Fig. 1) (8Ouattara M. Cunha E.B. Li X. Huang Y.S. Dixon D. Eichenbaum Z. Shr of group A Streptococcus is a new type of composite NEAT protein involved in sequestering haem from methaemoglobin.Mol. Microbiol. 2010; 78 (20807204): 739-75610.1111/j.1365-2958.2010.07367.xCrossref PubMed Scopus (53) Google Scholar, 11Hoshino M. Nakakido M. Nagatoishi S. Aikawa C. Nakagawa I. Tsumoto K. Biophysical characterization of the interaction between heme and proteins responsible for heme transfer in Streptococcus pyogenes.Biochem. Biophys. Res. Commun. 2017; 493 (28919415): 1109-111410.1016/j.bbrc.2017.09.055Crossref PubMed Scopus (4) Google Scholar). Released hemin is then bound by residues located within Shr’s C-terminal region (CTR) (residues 365–1275), which contains two hemin-binding NEAT domains (NEAT1 and NEAT2) that are separated from one another by a series of leucine-rich repeats (8Ouattara M. Cunha E.B. Li X. Huang Y.S. Dixon D. Eichenbaum Z. Shr of group A Streptococcus is a new type of composite NEAT protein involved in sequestering haem from methaemoglobin.Mol. Microbiol. 2010; 78 (20807204): 739-75610.1111/j.1365-2958.2010.07367.xCrossref PubMed Scopus (53) Google Scholar). Interestingly, similar to the staphylococcal IsdB and IsdH proteins, transfer experiments have shown that the isolated Shr protein increases the rate of hemin release from Hb in vitro, suggesting that the domains within the receptor function synergistically to extract hemin (9Lu C. Xie G. Liu M. Zhu H. Lei B. Direct heme transfer reactions in the group A Streptococcus heme acquisition pathway.PLoS ONE. 2012; 7 (22649539)e3755610.1371/journal.pone.0037556Crossref PubMed Scopus (16) Google Scholar). The NEAT domains within Shr can rapidly transfer hemin among one another, but only NEAT1 is able to efficiently transfer hemin to Shp (55Ouattara M. Pennati A. Devlin D.J. Huang Y.S. Gadda G. Eichenbaum Z. Kinetics of heme transfer by the Shr NEAT domains of group A Streptococcus.Arch. Biochem. Biop" @default.
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• W2897024970 title "The Streptococcus pyogenes Shr protein captures human hemoglobin using two structurally unique binding domains" @default.
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