Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Jedrzejas, Mark J.

doi:10.1007/s00018-007-7125-8

Cited by 46 publications

(37 citation statements)

References 154 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The overall structure, (␣/␣) 6 -barrel, of SagUGL in the C2 crystal was very similar to the previously determined structure (22) (Fig. 2A), although residues 151-171 were not assigned because of disorder.…”

Section: Resultssupporting

confidence: 79%

Structural Determinants in Streptococcal Unsaturated Glucuronyl Hydrolase for Recognition of Glycosaminoglycan Sulfate Groups

Nakamichi¹,

Maruyama²,

Mikami

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pathogenic Streptococcus agalactiae produces polysaccharide lyases and unsaturated glucuronyl hydrolase (UGL), which are prerequisite for complete degradation of mammalian extracellular matrices, including glycosaminoglycans such as chondroitin and hyaluronan. Unlike the Bacillus enzyme, streptococcal UGLs prefer sulfated glycosaminoglycans. Here, we show the loop flexibility for substrate binding and structural determinants for recognition of glycosaminoglycan sulfate groups in S. agalactiae UGL (SagUGL). UGL also degraded unsaturated heparin disaccharides; this indicates that the enzyme released unsaturated iduronic and glucuronic acids from substrates. We determined the crystal structures of SagUGL wild-type enzyme and both substrate-free and substratebound D175N mutants by x-ray crystallography and noted that the loop over the active cleft exhibits flexible motion for substrate binding. Several residues in the active cleft bind to the substrate, unsaturated chondroitin disaccharide with a sulfate group at the C-6 position of GalNAc residue. The sulfate group is hydrogen-bonded to Ser-365 and Ser-368 and close to Lys-370. As compared with wild-type enzyme, S365H, S368G, and K370I mutants exhibited higher Michaelis constants toward the substrate. The conversion of SagUGL to Bacillus sp. GL1 UGL-like enzyme via site-directed mutagenesis demonstrated that Ser-365 and Lys-370 are essential for direct binding and for electrostatic interaction, respectively, for recognition of the sulfate group by SagUGL. Molecular conversion was also achieved in SagUGL Arg-236 with an affinity for the sulfate group at the C-4 position of the GalNAc residue. These residues binding to sulfate groups are frequently conserved in pathogenic bacterial UGLs, suggesting that the motif "R-//-SXX(S)XK" (where the hyphen and slash marks in the motif indicate the presence of over 100 residues in the enzyme and parentheses indicate that Ser-368 makes little contribution to enzyme activity) is crucial for degradation of sulfated glycosaminoglycans.

show abstract

Section: Resultssupporting

confidence: 79%

Structural Determinants in Streptococcal Unsaturated Glucuronyl Hydrolase for Recognition of Glycosaminoglycan Sulfate Groups

Nakamichi¹,

Maruyama²,

Mikami

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Like many bacteria, pneumococci use hyaluronan lyase to degrade major components of the extracellular matrix (ECM), hyaluronan, and certain chondroitins, thereby facilitating invasive disease (215). The importance of hyaluronan lyase for the development of invasive pneumococcal disease was demonstrated in mice, as intranasally administered hyaluronidase adjuvant enhanced the development of invasive disease after an otherwise noninvasive intranasal inoculation of pneumococci (552).…”

Section: Extracellular Matrixmentioning

confidence: 99%

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

et al. 2011

View full text Add to dashboard Cite

SUMMARY Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae , which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.

show abstract

“…Pneumolysin is the thiol-activated cytolysin produced by S. pneumoniae that enables the bacterium to penetrate the host's physical defenses through its cytotoxic effect on epithelial cells, thus facilitating carriage and disease (28). PspA is a cell wall-associated protein that plays a role in inhibiting complement-mediated opsonization (7,33) and can prevent lactoferrin-mediated clearance (19). In contrast to Ply, PspA shows structural diversity between pneumococcal strains and has been classified into three families based on the sequence variability of the most C-terminal 100 amino acids of the N-terminal domain of PspA.…”

mentioning

confidence: 99%

Maternal Antibodies to Pneumolysin but Not to Pneumococcal Surface Protein A Delay Early Pneumococcal Carriage in High-Risk Papua New Guinean Infants

Francis

Richmond

Pomat

et al. 2009

Clin Vaccine Immunol

View full text Add to dashboard Cite

Immunization of pregnant women can be an efficient strategy to induce early protection in infants in developing countries. Pneumococcal protein-based vaccines may have the capacity to induce pneumococcal serotype-independent protection. To understand the potential of maternal pneumococcal protein-specific antibodies in infants in high-risk areas, we studied the placental transfer of naturally acquired antibodies to pneumolysin (Ply) and pneumococcal surface protein A family 1 and 2 (PspA1 and PspA2) in relation to onset of pneumococcal nasopharyngeal carriage in infants in Papua New Guinea (PNG). In this study, 76% of the infants carried Streptococcus pneumoniae in the upper respiratory tract within the first month of life, at a median age of 19 days. Maternal and cord blood antibody titers to Ply ( ‫؍‬ 0.824, P < 0.001), PspA1 ( ‫؍‬ 0.746, P < 0.001), and PspA2 ( ‫؍‬ 0.631, P < 0.001) were strongly correlated. Maternal pneumococcal carriage (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.25 to 5.39) and younger maternal age (HR, 0.74; 95% CI, 0.54 to 1.00) were independent risk factors for early carriage, while higher cord Ply-specific antibody titers predicted a significantly delayed onset (HR, 0.71; 95% CI, 0.52 to 1.00) and cord PspA1-specific antibodies a significantly younger onset of carriage in PNG infants (HR, 1.57; 95% CI, 1.03 to 2.40). Maternal vaccination with a pneumococcal protein-based vaccine should be considered as a strategy to protect high-risk infants against pneumococcal disease by reducing carriage risks in both mothers and infants.

show abstract

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Cited by 46 publications

References 154 publications

Structural Determinants in Streptococcal Unsaturated Glucuronyl Hydrolase for Recognition of Glycosaminoglycan Sulfate Groups

Structural Determinants in Streptococcal Unsaturated Glucuronyl Hydrolase for Recognition of Glycosaminoglycan Sulfate Groups

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Maternal Antibodies to Pneumolysin but Not to Pneumococcal Surface Protein A Delay Early Pneumococcal Carriage in High-Risk Papua New Guinean Infants

Contact Info

Product

Resources

About