PA-IIL

From CFGparadigms

PA-IIL (Pseudomonas lectin II, LecB) is a cytoplasmic lectin produced in Pseudomonas aruginosa under the control of quorum sensing. It is a virulence factor involved in binding of human tissues such as epithelial lung of cystic fibrosis patients^[1]. The role of PA-IIL in pathogenesis has been highlighted, since interfering with PA-IIL binding site reduces the mortality of P. aeruginosa induced-pneumonia in a murine model^[2]. The paradigm is unique among glycan-binding proteins (GBPs) in that it contains two cationic ions in the carbohydrate binding site that result in unusual high affinity for the carbohydrate target^[3][4][5]. The preferred glycan ligand of PA-IIL is the trisaccharide Lewis a^[6]. PA-IIL-like lectins have been characterized in other opportunistic bacteria such as Ralstonia solanacearum^[7], Chromobacterium violaceum^[8], and Burkholderia cenocepacia^[9][10], albeit with some variations in the fine specificity. Starting from the results obtained with the help of CFG tools, major efforts are devoided in collaboration with carbohydrate chemists in order to design anti-bacterial new glyco-derived compounds that bind to PA-IIL with high affinity^[11].

Contents 1 CFG Participating Investigators contributing to the understanding of this paradigm 2 Progress toward understanding this GBP paradigm 2.1 Carbohydrate ligands 2.2 Cellular expression of GBP and ligands 2.3 Biosynthesis of ligands 2.4 Structure 2.5 Biological roles of GBP-ligand interaction 3 CFG resources used in investigations 3.1 Glycan profiling 3.2 Glycogene microarray 3.3 Knockout mouse lines 3.4 Glycan array 4 Related GBPs 5 References 6 Acknowledgements

CFG Participating Investigators contributing to the understanding of this paradigm

CFG Participating Investigators (PIs) have made major contribution to the understanding of the structure/specificity relationship of PA-IIL and PA-IIL-like proteins. These include: Anne Imberty, Remy Loris, Michaela Wimmerova

Progress toward understanding this GBP paradigm

This section documents what is currently known about PA-IIL, its carbohydrate ligand(s), and how they interact to mediate cell communication.

Carbohydrate ligands

PA-IIL is a fucose-specific lectin that also recognises mannose residues.
The high affinity ligand for PA-IIL has been deduced from glycan microarray screening on the CFG microarray[1] to be Galβ1-4(Fucα1-4)GlcNAc [Lewis a] ^[4][6][12]

Cellular expression of GBP and ligands

PA-IIL is produced in Pseudomonas aruginosa, and binds ligands in human tissues, including epithelial lung.

Biosynthesis of ligands

Lewis a synthesis requires the addition of α1-4 fucose to the sub-terminal GlcNAc residue on a type 1 chain. Addition of the α1-4 fucose is catalyzed exclusively by fucosyltransferase FUT3 [2].

Structure

PA-IIL is a tetrameric lectin. Each monomer consists of a β-sandwich and contains two calcium ions that interact directly with the carbohydrate ligand. Crystal structures have been determined for PA-IIL alone, and its complex with fucose, with related monosaccharides, and with complex fucosylated oligosaccharides.

Information on crystal structures of PA-IIL and links to PDB are available at PA-IIL page of 3D-lectin database

Biological roles of GBP-ligand interaction

PA-IIL, a virulence factor that binds human tissues such as epithelial lung of cystic fibrosis patients^[1], has roles in pathogenesis ^[2].

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for PA-IIL.

Glycan profiling

Glycogene microarray

PA-IIL is not represented on the CFG microarrays, which only contain probes for mouse and human glycogenes.

Knockout mouse lines

Not applicable.

Glycan array

The specificity of PA-IIl and related proteins was determined through glycan array analysis (click here and here).

Related GBPs

CV-IIL (CFG data), RS-IIL (CFG data), BC2L-A, BC2L-B (CFG data), BC2L-C (CFG data).

References

1. ↑ ^{1.0 1.1} Imberty, A., Wimmerova, M., Mitchell, E. P. & Gilboa-Garber, N. (2004). Structures of the lectins from Pseudomonas aeruginosa: Insights into molecular basis for host glycan recognition. Microb. Infect. 6, 222-229.
2. ↑ ^{2.0 2.1} Chemani, C., Imberty, A., de Bentzman, S., Pierre, P., Wimmerová, M., Guery, B. P. & Faure, K. (2009). Role of LecA and LecB lectins in Pseudomonas aeruginosa induced lung injury and effect of carbohydrates ligands. Infect. Immun. 77, 2065-2075.
3. ↑ Loris, R., Tielker, D., Jaeger, K.-E. & Wyns, L. (2003). Structural basis of carbohydrate recognition by the lectin LecB from Pseudomonas aeruginosa. J. Mol. Biol. 331, 861-870.
4. ↑ ^{4.0 4.1} Mitchell, E., Houles, C., Sudakevitz, D., Wimmerova, M., Gautier, C., Pérez, S., Wu, A. M., Gilboa-Garber, N. & Imberty, A. (2002). Structural basis for oligosaccharide-mediated adhesion of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. Nature Struct. Biol. 9, 918-921.
5. ↑ Mitchell, E. P., Sabin, C., Šnajdrová, L., Pokorná, M., Perret, S., Gautier, C., Hofr, C., Gilboa-Garber, N., Koča, J., Wimmerová, M. & Imberty, A. (2005). High affinity fucose binding of Pseudomonas aeruginosa lectin PA-IIL: 1.0 Å resolution crystal structure of the complex combined with thermodynamics and computational chemistry approaches. Proteins: Struct. Funct. Bioinfo. 58, 735-748.
6. ↑ ^{6.0 6.1} Perret, S., Sabin, C., Dumon, C., Pokorná, M., Gautier, C., Galanina, O., Ilia, S., Bovin, N., Nicaise, M., Desmadril, M., Gilboa-Garber, N., Wimmerova, M., Mitchell, E. P. & Imberty, A. (2005). Structural basis for the interaction between human milk oligosaccharides and the bacterial lectin PA-IIL of Pseudomonas aeruginosa. Biochem. J. 389, 325-332.
7. ↑ Sudakevitz, D., Kostlanova, N., Blatman-Jan, G., Mitchell, E. P., Lerrer, B., Wimmerova, M., Katcof, f. D. J., Imberty, A. & Gilboa-Garber, N. (2004). A new Ralstonia solanacearum high affinity mannose-binding lectin RS-IIL structurally resembling the Pseudomonas aeruginosa fucose-specific lectin PA-IIL. Mol. Microbiol. 52, 691-700.
8. ↑ Pokorná, M., Cioci, G., Perret, S., Rebuffet, E., Kostlánová, N., Adam, J., Gilboa-Garber, N., Mitchell, E. P., Imberty, A. & Wimmerová, M. (2006). Unusual entropy driven affinity of Chromobacterium violaceum lectin CV-IIL towards fucose and mannose. Biochemistry 45, 7501-7510.
9. ↑ Lameignere, E., Malinovská, L., Sláviková, M., Duchaud, E., Mitchell, E. P., Varrot, A., Šedo, O., Imberty, A. & Wimmerová, M. (2008). Structural basis for mannose recognition by a lectin from opportunistic bacteria Burkholderia cenocepacia. Biochem. J. 411, 307-318.
10. ↑ Lameignere, E., Shiao, T. C., Roy, R., Wimmerová, M., Dubreuil, F., Varrot, A. & Imberty, A. (2010). Structural basis of the affinity for oligomannosides and analogs displayed by BC2L-A, a Burkholderia cenocepacia soluble lectin. Glycobiology 20, 87-98.
11. ↑ Imberty, A., Chabre, Y. M. & Roy, R. (2008). Glycomimetics and glycodendrimers as high affinity microbial antiadhesins. Chemistry 14, 7490-7499.
12. ↑ Marotte K, Sabin C, Preville C, Moume-Pymbock M, Wimmerova M, Mitchell EP, Imberty A, Roy R. (2008) X-ray Structures and thermodynamics of the interaction of PA-IIL from Pseudomonas aeruginosa with disaccharide derivatives. ChemMedChem 10,1328-1338.

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Anne Imberty and Micha Wimmerova