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Patrick J Venables - One of the best experts on this subject based on the ideXlab platform.
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immunization with porphyromonas gingivalis Enolase induces autoimmunity to mammalian α Enolase and arthritis in dr4 ie transgenic mice
Arthritis & Rheumatism, 2011Co-Authors: Andrew J Kinloch, Natalia Wegner, Saba Alzabin, William Brintnell, Elizabeth Wilson, Lillian Barra, David A Bell, Ewa Cairns, Patrick J VenablesAbstract:Objective To examine the hypothesis that the subset of rheumatoid arthritis (RA) characterized by antibodies to citrullinated α-Enolase is mediated by Porphyromonas gingivalis Enolase in the context of DR4 alleles. Methods Recombinant human α-Enolase and P gingivalis Enolase, either citrullinated or uncitrullinated, were used to immunize DR4-IE–transgenic mice and control mice (class II major histocompatibility complex–deficient [class II MHC−/−] and C57BL/6 wild-type mice). Arthritis was quantified by measurement of ankle swelling in the hind paws and histologic examination. Serum IgG reactivity with α-Enolase and citrullinated α-Enolase was assayed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Antibodies to peptide 1 of citrullinated α-Enolase (CEP-1) and its arginine-bearing control peptide, REP-1, were also assessed by ELISA. Results Significant hind-ankle swelling (≥0.3 mm) occurred in DR4-IE–transgenic mice immunized with citrullinated human α-Enolase (9 of 12 mice), uncitrullinated human α-Enolase (9 of 12 mice), citrullinated P gingivalis Enolase (6 of 6 mice), and uncitrullinated P gingivalis Enolase (6 of 6 mice). Swelling peaked on day 24. None of the control groups developed arthritis. The arthritic joints showed synovial hyperplasia and erosions, but there was a paucity of leukocyte infiltration. Antibodies to human α-Enolase, both citrullinated and unmodified, and to CEP-1 and REP-1 were detectable in all immunized mice except the class II MHC−/− control mice. Conclusion This is the first animal model that links an immune response to P gingivalis Enolase to an important subset of RA, defined by antibodies to citrullinated α-Enolase in the context of DR4. The fact that arthritis and anti–CEP-1 antibodies were induced independent of citrullination of the immunizing antigen suggests that the unmodified form of α-Enolase may be important in initiating the corresponding subset of human RA.
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periodontitis in ra the citrullinated Enolase connection
Nature Reviews Rheumatology, 2010Co-Authors: Karin Lundberg, Natalia Wegner, Tulay Yucellindberg, Patrick J VenablesAbstract:Antibodies to citrullinated Enolase define a subset of rheumatoid arthritis (RA) associated with smoking and DR4 alleles. In this Perspectives article, the authors review epidemiological and genetic links between periodontitis (a disease in whichPorphyromonas gingivalis is a major pathogen) and RA and propose that that the association might be causal, due to molecular mimicry between epitopes on host and P. gingivaliscitrullinated Enolases driving the autoimmune response. Autoimmunity in rheumatoid arthritis (RA) is characterized by an antibody response to citrullinated proteins. Two of the risk factors for RA—HLA-DRB1 shared epitope alleles and smoking—are also associated with periodontitis, which is largely, but not exclusively, caused by Porphyromonas gingivalis infection. Furthermore, RA and periodontitis have a similar pathophysiology, characterized by destructive inflammation. The citrullination of proteins by P. gingivalis and the subsequent generation of autoantigens that drive autoimmunity in RA represents a possible causative link between these two diseases. Antibodies directed towards the immunodominant epitope of human citrullinated α-Enolase cross-react with a conserved sequence on citrullinated P. gingivalis Enolase. On the basis of this cross-reactivity, in this Perspectives article we explore the hypothesis of molecular mimicry in the etiology of RA, with citrullinated Enolase as the specific antigen involved.
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antibodies to citrullinated α Enolase peptide 1 are specific for rheumatoid arthritis and cross react with bacterial Enolase
Arthritis & Rheumatism, 2008Co-Authors: Karin Lundberg, Natalia Wegner, Andrew Kinloch, Benjamin A Fisher, Robin Wait, P Charles, Ted R Mikuls, Patrick J VenablesAbstract:Objective To map the antibody response to human citrullinated α-Enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity with bacterial Enolase. Methods Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated α-Enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial Enolase was investigated by immunoblotting. Results An immunodominant peptide, citrullinated α-Enolase peptide 1, was identified. Antibodies to this epitope were observed in 37–62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with Enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated α-Enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2 = 0.803, P < 0.0001). Affinity-purified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis Enolase. Conclusion We have identified an immunodominant epitope in citrullinated α-Enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial Enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.
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antibodies to citrullinated alpha Enolase peptide 1 are specific for rheumatoid arthritis and cross react with bacterial Enolase
Arthritis & Rheumatism, 2008Co-Authors: Karin Lundberg, Natalia Wegner, Andrew J Kinloch, Benjamin A Fisher, Robin Wait, P Charles, Ted R Mikuls, Patrick J VenablesAbstract:Objective To map the antibody response to human citrullinated α-Enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity with bacterial Enolase. Methods Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated α-Enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial Enolase was investigated by immunoblotting. Results An immunodominant peptide, citrullinated α-Enolase peptide 1, was identified. Antibodies to this epitope were observed in 37–62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with Enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated α-Enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2 = 0.803, P < 0.0001). Affinity-purified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis Enolase. Conclusion We have identified an immunodominant epitope in citrullinated α-Enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial Enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.
William Martin - One of the best experts on this subject based on the ideXlab platform.
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Enolase from trypanosoma brucei from the amitochondriate protist mastigamoeba balamuthi and from the chloroplast and cytosol of euglena gracilis pieces in the evolutionary puzzle of the eukaryotic glycolytic pathway
Molecular Biology and Evolution, 2000Co-Authors: Véronique Hannaert, Marieastrid Albert, Molnár Miklós, Terry Gaasterland, Christoph Wilhelm Sensen, Henner Brinkmann, Paul A M Michels, Ulrich Nowitzki, William MartinAbstract:Genomic or cDNA clones for the glycolytic enzyme Enolase were isolated from the amitochondriate pelobiont MASTIGAMOEBA: balamuthi, from the kinetoplastid TRYPANOSOMA: brucei, and from the euglenid EUGLENA: gracilis. Clones for the cytosolic enzyme were found in all three organisms, whereas EUGLENA: was found to also express mRNA for a second isoenzyme that possesses a putative N-terminal plastid-targeting peptide and is probably targeted to the chloroplast. Database searching revealed that ARABIDOPSIS: also possesses a second Enolase gene that encodes an N-terminal extension and is likely targeted to the chloroplast. A phylogeny of Enolase amino acid sequences from 6 archaebacteria, 24 eubacteria, and 32 eukaryotes showed that the MASTIGAMOEBA: Enolase tended to branch with its homologs from TRYPANOSOMA: and from the amitochondriate protist Entamoeba histolytica. The compartment-specific isoenzymes in EUGLENA: arose through a gene duplication independent of that which gave rise to the compartment-specific isoenzymes in Arabidopsis, as evidenced by the finding that the EUGLENA: Enolases are more similar to the homolog from the eubacterium Treponema pallidum than they are to homologs from any other organism sampled. In marked contrast to all other glycolytic enzymes studied to date, Enolases from all eukaryotes surveyed here (except EUGLENA:) are not markedly more similar to eubacterial than to archaebacterial homologs. An intriguing indel shared by Enolase from eukaryotes, from the archaebacterium Methanococcus jannaschii, and from the eubacterium Campylobacter jejuni maps to the surface of the three-dimensional structure of the enzyme and appears to have occurred at the same position in parallel in independent lineages.
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Enolase from trypanosoma brucei from the amitochondriate protist mastigamoeba balamuthi and from the chloroplast and cytosol of euglena gracilis pieces in the evolutionary puzzle of the eukaryotic glycolytic pathway
Molecular Biology and Evolution, 2000Co-Authors: Véronique Hannaert, Marieastrid Albert, Molnár Miklós, Terry Gaasterland, Christoph Wilhelm Sensen, Henner Brinkmann, Paul A M Michels, Ulrich Nowitzki, William MartinAbstract:Genomic or cDNA clones for the glycolytic enzyme Enolase were isolated from the amitochondriate pelobiont MASTIGAMOEBA: balamuthi, from the kinetoplastid TRYPANOSOMA: brucei, and from the euglenid EUGLENA: gracilis. Clones for the cytosolic enzyme were found in all three organisms, whereas EUGLENA: was found to also express mRNA for a second isoenzyme that possesses a putative N-terminal plastid-targeting peptide and is probably targeted to the chloroplast. Database searching revealed that ARABIDOPSIS: also possesses a second Enolase gene that encodes an N-terminal extension and is likely targeted to the chloroplast. A phylogeny of Enolase amino acid sequences from 6 archaebacteria, 24 eubacteria, and 32 eukaryotes showed that the MASTIGAMOEBA: Enolase tended to branch with its homologs from TRYPANOSOMA: and from the amitochondriate protist Entamoeba histolytica. The compartment-specific isoenzymes in EUGLENA: arose through a gene duplication independent of that which gave rise to the compartment-specific isoenzymes in Arabidopsis, as evidenced by the finding that the EUGLENA: Enolases are more similar to the homolog from the eubacterium Treponema pallidum than they are to homologs from any other organism sampled. In marked contrast to all other glycolytic enzymes studied to date, Enolases from all eukaryotes surveyed here (except EUGLENA:) are not markedly more similar to eubacterial than to archaebacterial homologs. An intriguing indel shared by Enolase from eukaryotes, from the archaebacterium Methanococcus jannaschii, and from the eubacterium Campylobacter jejuni maps to the surface of the three-dimensional structure of the enzyme and appears to have occurred at the same position in parallel in independent lineages.
Zhonghuai Xiang - One of the best experts on this subject based on the ideXlab platform.
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cDNA cloning and expression pattern of two Enolase genes from the Chinese oak silkworm, Antheraea pernyi
2016Co-Authors: Yanqun Liu, Huan Wang, Runxi Xia, Haolei Wan, Li Qin, Defu Jiang, Zhonghuai XiangAbstract:In this study, two Enolase genes were isolated and charac-terized from the Chinese oak silkworm, Antheraea perny, which were designated as Enolase I and II, respectively. The Enolase I cDNA sequence was 1712 bp with an open reading frame (ORF) of 1302 bp encoding 433 amino acids. The Enolase II cDNA sequence was 1549 bp with an ORF of 1296 bp encoding 431 amino acids. The amino acid sequences of the two genes share several conserved features/sites of Enolase. Antheraea pernyi Enolase I shows 93%–97 % sequence identity to Enolases of lepidopterans available to date, 75%–82 % identity to Enolases of other invertebrates, 60%–72 % identity to Enolases of other organisms including vertebrates, plants, and fungi. Antheraea pernyi Enolase II shows 84 % identity to Bombyx mori Enolase II, but 60 % identity to A. pernyi Enolase I. I
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cDNA cloning and expression pattern of two Enolase genes from the Chinese oak silkworm, Antheraea pernyi.
Acta biochimica et biophysica Sinica, 2010Co-Authors: Yanqun Liu, Huan Wang, Runxi Xia, Haolei Wan, Li Qin, Defu Jiang, Zhonghuai XiangAbstract:In this study, two Enolase genes were isolated and characterized from the Chinese oak silkworm, Antheraea perny, which were designated as Enolase I and II, respectively. The Enolase I cDNA sequence was 1712 bp with an open reading frame (ORF) of 1302 bp encoding 433 amino acids. The Enolase II cDNA sequence was 1549 bp with an ORF of 1296 bp encoding 431 amino acids. The amino acid sequences of the two genes share several conserved features/sites of Enolase. Antheraea pernyi Enolase I shows 93%-97% sequence identity to Enolases of lepidopterans available to date, 75%-82% identity to Enolases of other invertebrates, 60%-72% identity to Enolases of other organisms including vertebrates, plants, and fungi. Antheraea pernyi Enolase II shows 84% identity to Bombyx mori Enolase II, but 60% identity to A. pernyi Enolase I. In the phylogenetic tree, Enolase II sequences from A. pernyi and B. mori were clearly separated from the majority of Enolase sequences of higher organisms including A. pernyi and B. mori Enolase I sequences. By sequence comparisons and phylogenetic analysis, we suggest that Enolase II from A. pernyi and B. mori may be a new member of the Enolase superfamily. Antheraea pernyi Enolase I mRNA was found in all tested tissues whereas Enolase II mRNA was expressed specifically in the spermaries and ovaries, suggesting that the product of Enolase II gene may be related to reproduction. The transcript abundance of A. pernyi Enolase I gene was significantly down-regulated after cold shock and significantly up-regulated after heat shock, suggesting that A. pernyi Enolase I gene may be inducible by temperature stress.
Véronique Hannaert - One of the best experts on this subject based on the ideXlab platform.
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Enolase from trypanosoma brucei from the amitochondriate protist mastigamoeba balamuthi and from the chloroplast and cytosol of euglena gracilis pieces in the evolutionary puzzle of the eukaryotic glycolytic pathway
Molecular Biology and Evolution, 2000Co-Authors: Véronique Hannaert, Marieastrid Albert, Molnár Miklós, Terry Gaasterland, Christoph Wilhelm Sensen, Henner Brinkmann, Paul A M Michels, Ulrich Nowitzki, William MartinAbstract:Genomic or cDNA clones for the glycolytic enzyme Enolase were isolated from the amitochondriate pelobiont MASTIGAMOEBA: balamuthi, from the kinetoplastid TRYPANOSOMA: brucei, and from the euglenid EUGLENA: gracilis. Clones for the cytosolic enzyme were found in all three organisms, whereas EUGLENA: was found to also express mRNA for a second isoenzyme that possesses a putative N-terminal plastid-targeting peptide and is probably targeted to the chloroplast. Database searching revealed that ARABIDOPSIS: also possesses a second Enolase gene that encodes an N-terminal extension and is likely targeted to the chloroplast. A phylogeny of Enolase amino acid sequences from 6 archaebacteria, 24 eubacteria, and 32 eukaryotes showed that the MASTIGAMOEBA: Enolase tended to branch with its homologs from TRYPANOSOMA: and from the amitochondriate protist Entamoeba histolytica. The compartment-specific isoenzymes in EUGLENA: arose through a gene duplication independent of that which gave rise to the compartment-specific isoenzymes in Arabidopsis, as evidenced by the finding that the EUGLENA: Enolases are more similar to the homolog from the eubacterium Treponema pallidum than they are to homologs from any other organism sampled. In marked contrast to all other glycolytic enzymes studied to date, Enolases from all eukaryotes surveyed here (except EUGLENA:) are not markedly more similar to eubacterial than to archaebacterial homologs. An intriguing indel shared by Enolase from eukaryotes, from the archaebacterium Methanococcus jannaschii, and from the eubacterium Campylobacter jejuni maps to the surface of the three-dimensional structure of the enzyme and appears to have occurred at the same position in parallel in independent lineages.
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Enolase from trypanosoma brucei from the amitochondriate protist mastigamoeba balamuthi and from the chloroplast and cytosol of euglena gracilis pieces in the evolutionary puzzle of the eukaryotic glycolytic pathway
Molecular Biology and Evolution, 2000Co-Authors: Véronique Hannaert, Marieastrid Albert, Molnár Miklós, Terry Gaasterland, Christoph Wilhelm Sensen, Henner Brinkmann, Paul A M Michels, Ulrich Nowitzki, William MartinAbstract:Genomic or cDNA clones for the glycolytic enzyme Enolase were isolated from the amitochondriate pelobiont MASTIGAMOEBA: balamuthi, from the kinetoplastid TRYPANOSOMA: brucei, and from the euglenid EUGLENA: gracilis. Clones for the cytosolic enzyme were found in all three organisms, whereas EUGLENA: was found to also express mRNA for a second isoenzyme that possesses a putative N-terminal plastid-targeting peptide and is probably targeted to the chloroplast. Database searching revealed that ARABIDOPSIS: also possesses a second Enolase gene that encodes an N-terminal extension and is likely targeted to the chloroplast. A phylogeny of Enolase amino acid sequences from 6 archaebacteria, 24 eubacteria, and 32 eukaryotes showed that the MASTIGAMOEBA: Enolase tended to branch with its homologs from TRYPANOSOMA: and from the amitochondriate protist Entamoeba histolytica. The compartment-specific isoenzymes in EUGLENA: arose through a gene duplication independent of that which gave rise to the compartment-specific isoenzymes in Arabidopsis, as evidenced by the finding that the EUGLENA: Enolases are more similar to the homolog from the eubacterium Treponema pallidum than they are to homologs from any other organism sampled. In marked contrast to all other glycolytic enzymes studied to date, Enolases from all eukaryotes surveyed here (except EUGLENA:) are not markedly more similar to eubacterial than to archaebacterial homologs. An intriguing indel shared by Enolase from eukaryotes, from the archaebacterium Methanococcus jannaschii, and from the eubacterium Campylobacter jejuni maps to the surface of the three-dimensional structure of the enzyme and appears to have occurred at the same position in parallel in independent lineages.
Sven Hammerschmidt - One of the best experts on this subject based on the ideXlab platform.
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Enolase of streptococcus pneumoniae binds human complement inhibitor c4b binding protein and contributes to complement evasion
Journal of Immunology, 2012Co-Authors: Vaibhav Agarwal, Simone Bergmann, Sven Hammerschmidt, Sven Malm, Kristian Riesbeck, Anna M BlomAbstract:Streptococcus pneumoniae (pneumococcus) is a pathogen that causes severe local and life-threatening invasive diseases, which are associated with high mortality rates. Pneumococci have evolved several strategies to evade the host immune system, including complement to disseminate and to survive in various host niches. Thus, pneumococci bind complement inhibitors such as C4b-binding protein (C4BP) and factor H via pneumococcal surface protein C, thereby inhibiting the classical and alternative complement pathways. In this study, we identified the pneumococcal glycolytic enzyme Enolase, a nonclassical cell surface and plasminogen-binding protein, as an additional pneumococcal C4BP-binding protein. Furthermore, we demonstrated that human, but not mouse, C4BP bound pneumococci. Recombinant Enolase bound in a dose-dependent manner C4BP purified from plasma, and the interaction was reduced by increasing ionic strength. Enolase recruited C4BP and plasminogen, but not factor H, from human serum. Moreover, C4BP and plasminogen bound to different domains of Enolase as they did not compete for the interaction with Enolase. In direct binding assays with recombinant C4BP mutants lacking individual domains, two binding sites for Enolase were identified on the complement control protein (CCP) domain 1/CCP2 and CCP8 of the C4BP α-chains. C4BP bound to the Enolase retained its cofactor activity as determined by C4b degradation. Furthermore, in the presence of exogenously added Enolase, an increased C4BP binding to and subsequently decreased C3b deposition on pneumococci was observed. Taken together, pneumococci specifically interact with human C4BP via Enolase, which represents an additional mechanism of human complement control by this versatile pathogen.
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the nine residue plasminogen binding motif of the pneumococcal Enolase is the major cofactor of plasmin mediated degradation of extracellular matrix dissolution of fibrin and transmigration
Thrombosis and Haemostasis, 2005Co-Authors: Simone Bergmann, Manfred Rohde, Klaus T Preissner, Sven HammerschmidtAbstract:The glycolytic enzyme a-Enolase represents one of the nonclassical cell surface plasminogen-binding proteins of Streptococcus pneumoniae. In this study we investigated the impact of an internal plasminogen-binding motif of Enolase on degradation of extracellular matrix and pneumococcal transmigration. In the presence of host-derived plasminogen activators (PA) tissuetype PA or urokinase PA and plasminogen S. pneumoniae expressing wild-type Enolase efficiently degraded Matrigel or extracellular matrix (ECM). In contrast, amino acid substitutions in the nine residue plasminogen-binding motif of Enolase significantly reduced degradation of ECM or Matrigel by mutated pneumococci. Similarly, recombinant wild-type Enolase but not a mutated Enolase derivative that lacks plasminogen-binding activity efficiently degraded ECM and Matrigel, respectively. In particular, bacterial cell Enolase-bound plasmin potentiated dissolution of fibrin or laminin and transmigration of pneumococci through a fibrin matrix. In conclusion, these results provide evidence that the Enolase is the major plasminogen-binding protein of pneumococci and that the nine residue plasminogen-binding motif of Enolase is the key cofactor for plasmin-mediated pneumococcal degradation and transmigration through host ECM.
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plasmin ogen binding alpha Enolase from streptococcus pneumoniae crystal structure and evaluation of plasmin ogen binding sites
Journal of Molecular Biology, 2004Co-Authors: Stefanie Ehinger, Simone Bergmann, Sven Hammerschmidt, Wolfdieter Schubert, Dirk W HeinzAbstract:α-Enolases are ubiquitous cytoplasmic, glycolytic enzymes. In pathogenic bacteria, α-Enolase doubles as a surface-displayed plasmin(ogen)-binder supporting virulence. The plasmin(ogen)-binding site was initially traced to the two C-terminal lysine residues. More recently, an internal nine-amino acid motif comprising residues 248 to 256 was identified with this function. We report the crystal structure of α-Enolase from Streptococcus pneumoniae at 2.0 A resolution, the first structure both of a plasminogen-binding and of an octameric α-Enolase. While the dimer is structurally similar to other α-Enolases, the octamer places the C-terminal lysine residues in an inaccessible, inter-dimer groove restricting the C-terminal lysine residues to a role in folding and oligomerization. The nine residue plasminogen-binding motif, by contrast, is exposed on the octamer surface revealing this as the primary site of interaction between α-Enolase and plasminogen.