Structural and Functional Studies of Mammalian Peptidoglycan Recognition Protein, PGRP-S

Pradeep Sharma, Divya Dube, Satya Prakash Yadav, Mau Sinha, Punit Kaur, Sujata Sharma, Tej P Singh

Abstract


Peptidoglycan recognition proteins belong to a broad family of innate immunity molecules. Mammals have four types of peptidoglycan recognition proteins designated as PGRP-S, PGRP-Iα, PGRP-Iβ and PGRP-L. PGRP-S is expressed in the granular polymorphonuclear leucocytes, PGRP-Iα is secreted from liver into blood and PGRP-Iβ, and PGRP-L are expressed in the skin, eyes, salivary glands, throat, tongue, esophagus, stomach and intestine. Peptidoglycan recognition proteins protect the host by carrying out early recognition of invading microorganisms. They contain a common domain known as peptidoglycan recognition domain whose lengths in various PGRPs vary from 165 to 175 residues. PGRP-S consists of a single peptidoglycan recognition domain while PGRP-Iα, PGRP-Iβ and PGRP-L have additional domains. Thus, PGRP-S represents the binding component of peptidoglycan recognition proteins and for understanding the mode of binding of these proteins, structural studies of PGRP-S are essential. So far, two structures of PGRP-S, one from human and another from Camelus dromedarius are available. The structure of human PGRP-S is found to be in monomeric state while the structure of camel PGRP-S consists of two distinct dimers in which dimeric interfaces involve opposite faces of the monomer. The observed monomeric and double dimeric structures of PGRP-S are well correlated to the differences in amino acid sequences of human and camel proteins. The binding sites in the dimers of camel PGRP-S are located at the contact sites of two molecules, whereas in human PGRP-S, it is supported by the single molecule. As a result, the binding clefts in camel protein are formed more efficiently as compared to the human protein. However, tertiary structures of both camel and human proteins are almost identical, with an average root mean squares shift of 1.2 Å for the backbone atoms. Since the ligand binding clefts in camel protein appear to have been evolved with better binding potencies than the human protein, the camel PGRP-S could be exploited for beneficial therapeutic applications against bacterial infections.

Keywords


PGRP-S; CPGRP-S; HPGRP-S; Mycolic acid; Tuberculosis; LPS; PGN; LTA

Full Text:

PDF

References


J. A. Hoffmann. The immune response of Drosophila. Nature, Vol. 426, pp. 33–38, 2003.

C. C. Tydell, J. Yuan, P. Tran, and M. E. Selsted. Bovine peptidoglycan recognition protein-S: Antimicrobial activity, localization, secretion, and binding properties. J Immunol, Vol. 176, pp. 1154–1162, 2006.

S. Lebeer, J. Vanderleyden, S. C. De Keersmaecker. Host interactions of probiotic bacterial surface molecules: Comparison with commensals and pathogens. Nat Rev Microbiol, Vol. 8, pp. 171–184, 2010.

I. Ginsburg. Role of lipoteichoic acid in infection and inflammation. Lancet Infect Dis, Vol. 2, pp. 171–179, 2002.

M. Xu, Z. Wang, R. M. Locksley. Innate immune responses in peptidoglycan recognition protein L-deficient mice. Mol Cell Biol, Vol. 24, pp. 7949–7957, 2004.

P. J. Brennan. Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis. Tuberculosis, Vol. 83, pp. 91–97, 2003.

X. Lu, M. Wang, J. Qi, H. Wang, X. Li, D. Gupta, R. Dziarski. Peptidoglycan recognition proteins are a new class of human bactericidal proteins. J Biol Chem, Vol. 28, pp. 5895–5907, 2006.

R. Dziarski, K. A. Platt, E. Gelius, H. Steiner, D. Gupta. Defect in neutrophil killing and increased susceptibility to infection with nonpathogenic gram-positive bacteria in peptidoglycan recognition protein-S (PGRP-S)-deficient mice. Blood, Vol. 102, pp. 689–697, 2003.

D. Kang, G. Liu, A. Lundstrom, E. Gelius, H. Steiner. A peptidoglycan recognition protein in innate immunity conserved from insects to humans. Proc Natl Acad Sci U S A, Vol. 95, pp. 10078–10082, 1998.

S. R. Kappeler, C. Heuberger, Z. Farah, Z. Puhan. Expression of the peptidoglycan recognition protein, PGRP, in the lactating mammary gland. J Dairy Sci, Vol. 87, pp. 2660–2668, 2004.

J. Wang, V. Gusti, A. Saraswati, D. D. Lo. Convergent and divergent development among M cell lineages in mouse mucosal epithelium. J Immunol, Vol. 187, pp. 5277–5285, 2011.

D. Lo et al. Peptidoglycan recognition protein expression in mouse Peyer’s Patch follicle associated epithelium suggests functional specialization. Cell Immunol, Vol. 224, pp. 8–16, 2003.

H. Wang, D. Gupta, X. Li, R. Dziarski. Peptidoglycan recognition protein 2 (N-acetylmuramoyl-L-Ala amidase) is induced in keratinocytes by bacteria through the p38 kinase pathway. Infect Immun, Vol. 73, pp. 7216–7225, 2005.

C. Liu, Z. Xu, D. Gupta, R. Dziarski. Peptidoglycan recognition proteins: A novel family of four human innate

immunity pattern recognition molecules. J Biol Chem, Vol. 276, pp. 34686–34694, 2001.

R. Dziarski R and D. Gupta. The peptidoglycan recognition proteins (PGRPs). Genome Biol. Vol. 7, pp. 232, 2006.

P. Sharma et al. Structural basis of recognition of pathogen-associated molecular patterns and inhibition of proinflammatory cytokines by camel peptidoglycan recognition protein. J Biol Chem. Vol. 286, pp. 16208–16217, 2011.

P. Sharma, N. Singh, M. Sinha et al. Crystal structure of the peptidoglycan recognition protein at 1.8 Å resolution reveals dual strategy to combat infection through two independent functional homodimers. J Mol Biol, Vol. 378, pp. 923–932, 2008.

R. Guan, Q. Wang, E. J. Sundberg, R. A. Mariuzza. Crystal structure of human peptidoglycan recognition protein S (PGRP-S) at 1.70 Å resolution. J Mol Biol, Vol. 347, pp. 683–691, 2005.

P. Sharma, D. Dube, M. Sinha et al. Multiligand Specificity of Pathogen-associated Molecular Pattern-binding Site in Peptidoglycan Recognition Protein. J Biol Chem, Vol. 286, pp. 31723–31730, 2011.

P. Sharma, D. Dube, M. Sinha et al. Structural basis of heparin binding to camel peptidoglycan recognition protein-S. Int J Biochem Mol Biol, Vol. 3, pp. 86–94, 2012.

P. Sharma, S. Yamini, D. Dube et al. Structural studies on molecular interactions between camel peptidoglycan recognition protein, CPGRP-S, and peptidoglycan moieties N-acetylglucosamine and N-acetylmuramic acid. J Biol Chem, Vol. 287, pp. 22153–22164, 2012.

P. Sharma et al. Structural basis of the binding of fatty acids to peptidoglycan recognition protein, PGRP-S through second binding site. Arch Biochem Biophys, Vol. 529, pp. 1–10, 2013.

P. Sharma, et al. Structural insights into the dual strategy of recognition by peptidoglycan recognition protein, PGRP-S: structure of the ternary complex of PGRP-S with lipopolysaccharide and stearic acid. PLoS One, Vol. 8, pp. e53756, 2013.

R. M. Kini, H. J. Evans. A hypothetical structural role for proline residues in the flanking segments of proteinprotein interaction sites. Biochem Biophys Res Commun, Vol. 212, pp. 1115–1124, 1995.

E. Krissinel, K. Henrick. Inference of macromolecular assemblies from crystalline state. J Mol Biol, Vol. 372, pp. 774–797, 2007.

R. Guan, A. Roychowdhury, B. Ember, S. Kumar, G. J. Boons, R. A. Mariuzza. Structural basis for peptidoglycan binding by peptidoglycan recognition proteins. Proc Natl Acad Sci U S A, Vol. 101, pp. 17168–17173, 2004.


Refbacks

  • There are currently no refbacks.