The PGLYRP1 gene is highly expressed in bone marrow, circulating Polymorphonuclear leukocytes (PMLs), and in the corneal epithelium. The PGLYRP1 protein is primarily found in the granules of PMLs.
Structure
As with most PGRPs, PGLYRP1 has one carboxy-terminal type 2 amidase domain (also known as a PGRP domain) and consists of three alpha helices, five beta strands and coils, and has three pairs of conserved cysteins which form three disulphide bonds.[4] PGLYRP1 can form homodimers for its antimicrobial activity, and can complex with HSP70 for its cytotoxic activity.
Function
The PGLYRP1 protein plays an important role in the innate immune response. It is bactericidal against gram-positive bacteria such as S. aureus, S. epidermidis, and L. monocytogenes and generally has proinflammatory effects, inducing TNF-a and IFN-g in many tissues. PGLYRP-1 is also known to form a cytotoxic complex with HSP-70, suggesting it may also have a role in anti-cancer defense.[5] As a pathogen recognition protein with antimicrobial properties, PGLYRP-1 is suspected to play an important role in maintaining the gut microbial flora.
Mechanism of action
As an antimicrobial, the binding of PGLYRP1 to its target does not permeabilize the bacterial cell wall like defensins and other antimicrobial peptides. Instead, PGLYRP1 binding activates a bacterial stress response that causes the bacterium to shut down transcription and translation, and induces oxidative stress. As a cytotoxic agent, the PGLYRP1-HSP70 complex
Possible pathological role
In humans, single nuclear polymorphisms of the PGLYRP1 gene have been associated with the development of ulcerative colitis.[6]
In mice, the lack of PGLYRP1 is associated with increased susceptibility to infectious disease, but also decreased susceptibility to autoimmune disease. The lack of PGLYRP1 was found to have increased susceptibility to corneal infections, reduced corneal wound healing, and increased scarification of the cornea when infected by P. aeruginosa.[7] But PGLYRP1-deficient mice also had decreased severity of atopic dermatitis and contact dermatitis. and may play a role in the development of asthma.
↑Kibardin AV, Mirkina II, Zakeeva IR, Baranova EV, Georgiev GP, Kiselev SL (Apr 2003). "[Expression analysis of proteins encoded by genes of the tag7/tagL (PGRP-S,L) family in human peripheral blood cells]". Genetika. 39 (2): 244–9. PMID12669421.
Guan R, Wang Q, Sundberg EJ, Mariuzza RA (2005). "Crystal structure of human peptidoglycan recognition protein S (PGRP-S) at 1.70 A resolution". J. Mol. Biol. 347 (4): 683–91. doi:10.1016/j.jmb.2005.01.070. PMID15769462.
Guan R, Malchiodi EL, Wang Q, et al. (2004). "Crystal structure of the C-terminal peptidoglycan-binding domain of human peptidoglycan recognition protein Ialpha". J. Biol. Chem. 279 (30): 31873–82. doi:10.1074/jbc.M404920200. PMID15140887.
Grimwood J, Gordon LA, Olsen A, et al. (2004). "The DNA sequence and biology of human chromosome 19". Nature. 428 (6982): 529–35. doi:10.1038/nature02399. PMID15057824.
Sashchenko LP, Dukhanina EA, Yashin DV, et al. (2004). "Peptidoglycan recognition protein tag7 forms a cytotoxic complex with heat shock protein 70 in solution and in lymphocytes". J. Biol. Chem. 279 (3): 2117–24. doi:10.1074/jbc.M307513200. PMID14585845.
Wang ZM, Li X, Cocklin RR, et al. (2004). "Human peptidoglycan recognition protein-L is an N-acetylmuramoyl-L-alanine amidase". J. Biol. Chem. 278 (49): 49044–52. doi:10.1074/jbc.M307758200. PMID14506276.
Liu C, Xu Z, Gupta D, Dziarski R (2001). "Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules". J. Biol. Chem. 276 (37): 34686–94. doi:10.1074/jbc.M105566200. PMID11461926.
