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User: Julie Langlois/PsaA NCBI Accession: P42363.1 Uniprot Accesion: POA4G2 PDB ID: 3ZK7 Molecular weight: 34,538 kDa ^[1] /datasheet.php?products_id=1261287

Overview

PsaA protein

PsaA (Pneumococcal surface antigen A) is a multi-functional lipoprotein detected on all known serotypes of Streptococcus pneumoniae. This lipoprotein belongs to the ABC-type transport protein complex that transports Mn2+. The overall size of the protein approximated from its crystal structure is 40 by 40 by 70 Å. ABC means ATP binding complex. PsaA is also an adhesion factor that plays a major role in pneumococcal attachment to the host cell and virulence. PsaA is hidden beneath the cell wall. PsaA protein is involved in in colonization of the nasopharyngeal mucosal. This transporter is composed of the products of three genes, psaB (ATP-binding protein), psaC (integral membrane protein), and psaA (solute-binding lipoprotein), which are organized in an operon with a gene encoding PsaD, a thiol peroxidase ^[2].

Image:Linear structure PsaA.jpg Linear structure of PsaA

Between the first to the 24th amino acid namely the red motif there is the signal peptide and the second one is the Pfam motif^[3].

Zinc in excess has significant toxicity to bacteria because it is an important innate defence mechanism. There are many Zinc in human body. Manganese is important for the virulence, growth and proliferation of Streptococcus pneumoniae. Zinc could compete for Manganese binding. However Manganese has more affinity for PsaA than Zinc but Zinc is not transported by the ABC-transporter. Zinc competition reduces intracellular Manganse resulting in up-regulation of PsaBCA expression.

Streptococcus pneumoniae

Streptococcus pneumoniae is a Gram positive cocci (with a diameter from 0.5 to 1 μm) and a member of the genus Streptococcus. It can live under aerobic or anaerobic conditions. It resides in the nasopharynx of healthy carriers. However the bacterium may become pathogenic in elderly and immunocompromised people and children. Then it can spread to other locations and cause disease. Its genome of S. pneumoniae is a closed, circular DNA structure that contains between 2.0 and 2.1 million base pairs.^[4]

Structure

As a member of the Lipoprotein receptor-associated antigen I (LraI) family, the PsaA molecule contains four distinct regions. An N-terminal leader sequence of 20 amino acids holds an LxACy consensus sequence that is recognized and cleaved by signal peptidase II ^[5]. A lipid moiety (diacylglycerol ^[6]) is added to the cysteine residue and mediates the anchorage of the protein to the cytoplasmic membrane. Apart from this leader sequence, the rest of the protein consists of two twofold-pseudosymmetrical (β/α)4 sandwich domains, of which the β-strands of each domain form parallel β-sheets ^[7]. In total the two domains form two lobes connected via an α-helical linker which constitutes the solute-binding site ^[8].

This image shows the metal binding site in more detail, with the MntC residues and Manganese. Manganse ions are shown as purple spheres. We can see that Manganese interacts with Histine residues, Aspartique acid residues and Glutamique acid residues. The metal binding site is formed by the sidechains of residues His67, His139, Glu205, and Asp280. This site has tetrahedral coordination geometry. The amino acids His67 andHis139 interact with the metal via Nε2 nitrogen atoms. However, the carboxylate sidechains of Glu205 and Asp280 interact with the metal via their Oε1 and Oδ2 atoms. The atomic distance between His67 Nε2 and the metal is 1.99 Ắ while it is 2,01 Ắ for His 139 Nε2. It is 2,04 Ắ for Glu205 Oε1 and 2,02 Ắ for Asp280 Oδ2. The Oδ1 atom of Asp137 can form a hydrogen bond with Nδ1 of His139. Oδ1 atom of Asp65 can also form a hydrogen bond with His67 N.

This image shows the metal binding site in more detail, with MntC residues and Managanese and Zinc. Manganese ion is shown as a purple sphere and Zinc ion is shown as an orange sphere. 3D structure of PsaA with 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL (tris) and cadmium^[9]

Cadmium uptake reduces the millimolar cellular accumulation of manganese and zinc, and thereby increases sensitivity to oxidative stress ^[10].

This is a test to add a in the Sandbox

Protein-protein interaction

Function

Disease

Meningitis

Otitis

PsaA has been recognized to be involved in the adherence and virulence mechanisms of otitis media. Streptococcus pneumoniae is one of the main agents causing bacterial acute otitis media, directly or as complication of a viral upper respiratory tract infection. This disease is a highly prevalent pediatric disease worldwide. Hearing loss is a common problem associated with this disease. ^[11] Progress in vaccine development is most advanced for Streptococcus pneumoniae. Indeed, there is a seven-valent capsular-conjugate vaccine, PREVNAR® but it is rather non efficient for otitis media.^[12]

Pneumonia

PsaA protein is an adhesin which is involved in colonization of the nasopharyngeal mucosal. Moreover, alveolar pneumonia is caused by the spread of Streptococcus pneumoniae from nasopharynx. Therefore PsaA protein is involved in infection of pulmonary parenchyma by Streptococcus pneumoniae. Sometimes, Streptococcus pneumoniae pass into the blood and causes a bacteremia besides pneumonia.

Application in Biotechnology

PsaA is being actively evaluated as a component of a vaccin in formulations composed of pneumococcal common proteins. PsaA has been expressed as an E.coli recombinant protein, purified, and evaluated in a phase one clinical trial.

References

1. ↑ https://www.mybiosource.com/prods/Recombinant-Protein/Manganese-ABC-transporter-substrate-binding-lipoprotein-psaA/psaA
2. ↑ Moore RC. Investigational drug information is available to the pharmacist. Am J Hosp Pharm. 1979 Nov;36(11):1480, 1484. PMID:517531
3. ↑ http://string-db.org/cgi/network.pl?taskId=EA2jsQm5Sc5A
4. ↑ Bierman EL, Stein O, Stein Y. Lipoprotein uptake and metabolism by rat aortic smooth muscle cells in tissue culture. Circ Res. 1974 Jul;35(1):136-50. PMID:4366526
5. ↑ Yu Y, Chang, Xu H, Zhang X, Pan L, Xu C, Huang B, Zhou H, Li J, Guo J, Liu C. The virulence of Streptococcus pneumoniae partially depends on dprA. Braz J Microbiol. 2016 Dec 6. pii: S1517-8382(16)30151-4. doi:, 10.1016/j.bjm.2016.10.019. PMID:28011228 doi:http://dx.doi.org/10.1016/j.bjm.2016.10.019
6. ↑ PMID:PMC99024
7. ↑ PMID:PMC99024
8. ↑ Yu Y, Chang, Xu H, Zhang X, Pan L, Xu C, Huang B, Zhou H, Li J, Guo J, Liu C. The virulence of Streptococcus pneumoniae partially depends on dprA. Braz J Microbiol. 2016 Dec 6. pii: S1517-8382(16)30151-4. doi:, 10.1016/j.bjm.2016.10.019. PMID:28011228 doi:http://dx.doi.org/10.1016/j.bjm.2016.10.019
9. ↑ http://www.ebi.ac.uk/pdbe/entry/pdb/4UTO
10. ↑ http://www.nature.com/articles/ncomms7418
11. ↑ https://www.google.com/patents/US20130078254
12. ↑ Wald ER, Mason EO Jr, Bradley JS, Barson WJ, Kaplan SL. Acute otitis media caused by Streptococcus pneumoniae in children's hospitals between 1994 and 1997. Pediatr Infect Dis J. 2001 Jan;20(1):34-9. PMID:11176564