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== Tissue distribution and secretion ==
== Tissue distribution and secretion ==
PGLYRP3 has similar expression to PGLYRP4 ([[peptidoglycan recognition protein 4]]) but not identical.<ref name=":0" /><ref name=":2">{{Cite journal|last=Lu|first=Xiaofeng|last2=Wang|first2=Minhui|last3=Qi|first3=Jin|last4=Wang|first4=Haitao|last5=Li|first5=Xinna|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2006-03-03|title=Peptidoglycan recognition proteins are a new class of human bactericidal proteins|url=https://pubmed.ncbi.nlm.nih.gov/16354652|journal=The Journal of Biological Chemistry|volume=281|issue=9|pages=5895–5907|doi=10.1074/jbc.M511631200|issn=0021-9258|pmid=16354652}}</ref> PGLYRP3 is constitutively expressed in the skin, in the eye, and in the [[Mucous membrane|mucous membranes]] in the [[tongue]], [[throat]], and [[esophagus]], and at a much lower level in the remaining parts of the [[Gastrointestinal tract|intestinal tract]].<ref name=":0" /><ref name=":2" /><ref>{{Cite journal|last=Mathur|first=Punam|last2=Murray|first2=Beth|last3=Crowell|first3=Thomas|last4=Gardner|first4=Humphrey|last5=Allaire|first5=Normand|last6=Hsu|first6=Yen-Ming|last7=Thill|first7=Greg|last8=Carulli|first8=John P.|date=June 2004|title=Murine peptidoglycan recognition proteins PglyrpIalpha and PglyrpIbeta are encoded in the epidermal differentiation complex and are expressed in epidermal and hematopoietic tissues|url=https://pubmed.ncbi.nlm.nih.gov/15177568|journal=Genomics|volume=83|issue=6|pages=1151–1163|doi=10.1016/j.ygeno.2004.01.003|issn=0888-7543|pmid=15177568}}</ref><ref name=":3">{{Cite journal|last=Saha|first=Sukumar|last2=Jing|first2=Xuefang|last3=Park|first3=Shin Yong|last4=Wang|first4=Shiyong|last5=Li|first5=Xinna|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2010-08-19|title=Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma|url=https://pubmed.ncbi.nlm.nih.gov/20709292|journal=Cell Host & Microbe|volume=8|issue=2|pages=147–162|doi=10.1016/j.chom.2010.07.005|issn=1934-6069|pmc=2998413|pmid=20709292}}</ref> [[Bacteria]] and their products increase the expression of PGLYRP3 in [[Keratinocyte|keratinocytes]] and oral [[Epithelium|epithelial cells]].<ref name=":1" /><ref>{{Cite journal|last=Uehara|first=A.|last2=Sugawara|first2=Y.|last3=Kurata|first3=S.|last4=Fujimoto|first4=Y.|last5=Fukase|first5=K.|last6=Kusumoto|first6=S.|last7=Satta|first7=Y.|last8=Sasano|first8=T.|last9=Sugawara|first9=S.|last10=Takada|first10=H.|date=May 2005|title=Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via toll-like receptors, NOD1 and NOD2 in human oral epithelial cells|url=https://pubmed.ncbi.nlm.nih.gov/15839897|journal=Cellular Microbiology|volume=7|issue=5|pages=675–686|doi=10.1111/j.1462-5822.2004.00500.x|issn=1462-5814|pmid=15839897}}</ref> Mouse PGLYRP3 is also differentially expressed in the developing brain and this expression is influenced by the intestinal [[microbiome]].<ref>{{Cite journal|last=Arentsen|first=T.|last2=Qian|first2=Y.|last3=Gkotzis|first3=S.|last4=Femenia|first4=T.|last5=Wang|first5=T.|last6=Udekwu|first6=K.|last7=Forssberg|first7=H.|last8=Diaz Heijtz|first8=R.|date=February 2017|title=The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior|url=https://pubmed.ncbi.nlm.nih.gov/27843150|journal=Molecular Psychiatry|volume=22|issue=2|pages=257–266|doi=10.1038/mp.2016.182|issn=1476-5578|pmc=5285465|pmid=27843150}}</ref> PGLYRP3 is secreted and forms [[disulfide]]-linked dimers.<ref name=":2" />
PGLYRP3 has similar expression to PGLYRP4 ([[peptidoglycan recognition protein 4]]) but not identical.<ref name=":0" /><ref name=":2">{{Cite journal|last=Lu|first=Xiaofeng|last2=Wang|first2=Minhui|last3=Qi|first3=Jin|last4=Wang|first4=Haitao|last5=Li|first5=Xinna|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2006-03-03|title=Peptidoglycan recognition proteins are a new class of human bactericidal proteins|url=https://pubmed.ncbi.nlm.nih.gov/16354652|journal=The Journal of Biological Chemistry|volume=281|issue=9|pages=5895–5907|doi=10.1074/jbc.M511631200|issn=0021-9258|pmid=16354652}}</ref> PGLYRP3 is constitutively expressed in the skin, in the eye, and in the [[mucous membrane]]s in the [[tongue]], [[throat]], and [[esophagus]], and at a much lower level in the remaining parts of the [[Gastrointestinal tract|intestinal tract]].<ref name=":0" /><ref name=":2" /><ref>{{Cite journal|last=Mathur|first=Punam|last2=Murray|first2=Beth|last3=Crowell|first3=Thomas|last4=Gardner|first4=Humphrey|last5=Allaire|first5=Normand|last6=Hsu|first6=Yen-Ming|last7=Thill|first7=Greg|last8=Carulli|first8=John P.|date=June 2004|title=Murine peptidoglycan recognition proteins PglyrpIalpha and PglyrpIbeta are encoded in the epidermal differentiation complex and are expressed in epidermal and hematopoietic tissues|url=https://pubmed.ncbi.nlm.nih.gov/15177568|journal=Genomics|volume=83|issue=6|pages=1151–1163|doi=10.1016/j.ygeno.2004.01.003|issn=0888-7543|pmid=15177568}}</ref><ref name=":3">{{Cite journal|last=Saha|first=Sukumar|last2=Jing|first2=Xuefang|last3=Park|first3=Shin Yong|last4=Wang|first4=Shiyong|last5=Li|first5=Xinna|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2010-08-19|title=Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma|url=https://pubmed.ncbi.nlm.nih.gov/20709292|journal=Cell Host & Microbe|volume=8|issue=2|pages=147–162|doi=10.1016/j.chom.2010.07.005|issn=1934-6069|pmc=2998413|pmid=20709292}}</ref> [[Bacteria]] and their products increase the expression of PGLYRP3 in [[keratinocyte]]s and oral [[Epithelium|epithelial cells]].<ref name=":1" /><ref>{{Cite journal|last=Uehara|first=A.|last2=Sugawara|first2=Y.|last3=Kurata|first3=S.|last4=Fujimoto|first4=Y.|last5=Fukase|first5=K.|last6=Kusumoto|first6=S.|last7=Satta|first7=Y.|last8=Sasano|first8=T.|last9=Sugawara|first9=S.|last10=Takada|first10=H.|date=May 2005|title=Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via toll-like receptors, NOD1 and NOD2 in human oral epithelial cells|url=https://pubmed.ncbi.nlm.nih.gov/15839897|journal=Cellular Microbiology|volume=7|issue=5|pages=675–686|doi=10.1111/j.1462-5822.2004.00500.x|issn=1462-5814|pmid=15839897}}</ref> Mouse PGLYRP3 is also differentially expressed in the developing brain and this expression is influenced by the intestinal [[microbiome]].<ref>{{Cite journal|last=Arentsen|first=T.|last2=Qian|first2=Y.|last3=Gkotzis|first3=S.|last4=Femenia|first4=T.|last5=Wang|first5=T.|last6=Udekwu|first6=K.|last7=Forssberg|first7=H.|last8=Diaz Heijtz|first8=R.|date=February 2017|title=The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior|url=https://pubmed.ncbi.nlm.nih.gov/27843150|journal=Molecular Psychiatry|volume=22|issue=2|pages=257–266|doi=10.1038/mp.2016.182|issn=1476-5578|pmc=5285465|pmid=27843150}}</ref> PGLYRP3 is secreted and forms [[disulfide]]-linked dimers.<ref name=":2" />


== Structure ==
== Structure ==
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The C-terminal [[peptidoglycan]]-binding domain of human PGLYRP3 has been crystallized and its structure solved<ref name=":6">{{Cite journal|last=Guan|first=Rongjin|last2=Malchiodi|first2=Emilio L.|last3=Wang|first3=Qian|last4=Schuck|first4=Peter|last5=Mariuzza|first5=Roy A.|date=2004-07-23|title=Crystal structure of the C-terminal peptidoglycan-binding domain of human peptidoglycan recognition protein Ialpha|url=https://pubmed.ncbi.nlm.nih.gov/15140887|journal=The Journal of Biological Chemistry|volume=279|issue=30|pages=31873–31882|doi=10.1074/jbc.M404920200|issn=0021-9258|pmid=15140887}}</ref> and is similar to human PGLYRP1.<ref name=":7">{{Cite journal|last=Guan|first=Rongjin|last2=Wang|first2=Qian|last3=Sundberg|first3=Eric J.|last4=Mariuzza|first4=Roy A.|date=2005-04-08|title=Crystal structure of human peptidoglycan recognition protein S (PGRP-S) at 1.70 A resolution|url=https://pubmed.ncbi.nlm.nih.gov/15769462|journal=Journal of Molecular Biology|volume=347|issue=4|pages=683–691|doi=10.1016/j.jmb.2005.01.070|issn=0022-2836|pmid=15769462}}</ref> PGLYRP3 C-terminal PGRP domain contains a central β-sheet composed of five β-strands and three α-helices and N-terminal segment unique to PGRPs and not found in [[bacteriophage]] and [[Prokaryote|prokaryotic]] amidases.<ref name=":6" />
The C-terminal [[peptidoglycan]]-binding domain of human PGLYRP3 has been crystallized and its structure solved<ref name=":6">{{Cite journal|last=Guan|first=Rongjin|last2=Malchiodi|first2=Emilio L.|last3=Wang|first3=Qian|last4=Schuck|first4=Peter|last5=Mariuzza|first5=Roy A.|date=2004-07-23|title=Crystal structure of the C-terminal peptidoglycan-binding domain of human peptidoglycan recognition protein Ialpha|url=https://pubmed.ncbi.nlm.nih.gov/15140887|journal=The Journal of Biological Chemistry|volume=279|issue=30|pages=31873–31882|doi=10.1074/jbc.M404920200|issn=0021-9258|pmid=15140887}}</ref> and is similar to human PGLYRP1.<ref name=":7">{{Cite journal|last=Guan|first=Rongjin|last2=Wang|first2=Qian|last3=Sundberg|first3=Eric J.|last4=Mariuzza|first4=Roy A.|date=2005-04-08|title=Crystal structure of human peptidoglycan recognition protein S (PGRP-S) at 1.70 A resolution|url=https://pubmed.ncbi.nlm.nih.gov/15769462|journal=Journal of Molecular Biology|volume=347|issue=4|pages=683–691|doi=10.1016/j.jmb.2005.01.070|issn=0022-2836|pmid=15769462}}</ref> PGLYRP3 C-terminal PGRP domain contains a central β-sheet composed of five β-strands and three α-helices and N-terminal segment unique to PGRPs and not found in [[bacteriophage]] and [[Prokaryote|prokaryotic]] amidases.<ref name=":6" />


Human PGLYRP3 C-terminal PGRP domain, similar to PGLYRP1,<ref name=":7" /> has three pairs of [[Cysteine|cysteines]], which form three disulfide bonds at positions 178–300, 194–238, and 214–220.<ref name=":6" /> The Cys214–Cys220 disulfide is broadly conserved in [[invertebrate]] and [[vertebrate]] PRGPs, the Cys178–Cys300 disulfide is conserved in all mammalian PGRPs, and the Cys194–238 disulfide is unique to mammalian PGLYRP1, PGLYRP3, and PGLYRP4, but not found in the amidase-active PGLYRP2.<ref name=":0" /><ref name=":5" /><ref name=":6" /><ref name=":7" /> The structures of the entire PGLYRP3 molecule (with two PGRP domains) and of the disulfide-linked dimer are unknown.
Human PGLYRP3 C-terminal PGRP domain, similar to PGLYRP1,<ref name=":7" /> has three pairs of [[cysteine]]s, which form three disulfide bonds at positions 178–300, 194–238, and 214–220.<ref name=":6" /> The Cys214–Cys220 disulfide is broadly conserved in [[invertebrate]] and [[vertebrate]] PRGPs, the Cys178–Cys300 disulfide is conserved in all mammalian PGRPs, and the Cys194–238 disulfide is unique to mammalian PGLYRP1, PGLYRP3, and PGLYRP4, but not found in the amidase-active PGLYRP2.<ref name=":0" /><ref name=":5" /><ref name=":6" /><ref name=":7" /> The structures of the entire PGLYRP3 molecule (with two PGRP domains) and of the disulfide-linked dimer are unknown.


PGLYRP3 C-terminal PGRP domain contains peptidoglycan-binding site, which is a long cleft whose walls are formed by α-helix and five β-loops and the floor by a β-sheet. This site binds muramyl-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), but can also accommodate larger peptidoglycan fragments, such as disaccharide-pentapeptide.<ref name=":8">{{Cite journal|last=Guan|first=Rongjin|last2=Roychowdhury|first2=Abhijit|last3=Ember|first3=Brian|last4=Kumar|first4=Sanjay|last5=Boons|first5=Geert-Jan|last6=Mariuzza|first6=Roy A.|date=2004-12-07|title=Structural basis for peptidoglycan binding by peptidoglycan recognition proteins|url=https://pubmed.ncbi.nlm.nih.gov/15572450|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=101|issue=49|pages=17168–17173|doi=10.1073/pnas.0407856101|issn=0027-8424|pmc=535381|pmid=15572450}}</ref> Located opposite the peptidoglycan-binding cleft is a large [[Hydrophobe|hydrophobic]] groove, formed by residues 177–198 (the PGRP-specific segment).<ref name=":8" />
PGLYRP3 C-terminal PGRP domain contains peptidoglycan-binding site, which is a long cleft whose walls are formed by α-helix and five β-loops and the floor by a β-sheet. This site binds muramyl-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), but can also accommodate larger peptidoglycan fragments, such as disaccharide-pentapeptide.<ref name=":8">{{Cite journal|last=Guan|first=Rongjin|last2=Roychowdhury|first2=Abhijit|last3=Ember|first3=Brian|last4=Kumar|first4=Sanjay|last5=Boons|first5=Geert-Jan|last6=Mariuzza|first6=Roy A.|date=2004-12-07|title=Structural basis for peptidoglycan binding by peptidoglycan recognition proteins|url=https://pubmed.ncbi.nlm.nih.gov/15572450|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=101|issue=49|pages=17168–17173|doi=10.1073/pnas.0407856101|issn=0027-8424|pmc=535381|pmid=15572450}}</ref> Located opposite the peptidoglycan-binding cleft is a large [[Hydrophobe|hydrophobic]] groove, formed by residues 177–198 (the PGRP-specific segment).<ref name=":8" />
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The PGLYRP3 protein plays an important role in the innate immune responses.
The PGLYRP3 protein plays an important role in the innate immune responses.


=== '''Peptidoglycan binding''' ===
=== Peptidoglycan binding ===
PGLYRP3 binds peptidoglycan, a polymer of β(1-4)-linked [[N-Acetylglucosamine|''N''-acetylglucosamine]] (GlcNAc) and [[N-Acetylmuramic acid|''N''-acetylmuramic acid]] (MurNAc) cross-linked by short [[Peptide|peptides]], the main component of [[Bacteria|bacterial]] [[cell wall]].<ref name=":0" /><ref name=":2" /><ref name=":8" /><ref name=":9">{{Cite journal|last=Kumar|first=Sanjay|last2=Roychowdhury|first2=Abhijit|last3=Ember|first3=Brian|last4=Wang|first4=Qian|last5=Guan|first5=Rongjin|last6=Mariuzza|first6=Roy A.|last7=Boons|first7=Geert-Jan|date=2005-11-04|title=Selective recognition of synthetic lysine and meso-diaminopimelic acid-type peptidoglycan fragments by human peptidoglycan recognition proteins I{alpha} and S|url=https://pubmed.ncbi.nlm.nih.gov/16129677|journal=The Journal of Biological Chemistry|volume=280|issue=44|pages=37005–37012|doi=10.1074/jbc.M506385200|issn=0021-9258|pmid=16129677}}</ref><ref name=":10">{{Cite journal|last=Swaminathan|first=Chittoor P.|last2=Brown|first2=Patrick H.|last3=Roychowdhury|first3=Abhijit|last4=Wang|first4=Qian|last5=Guan|first5=Rongjin|last6=Silverman|first6=Neal|last7=Goldman|first7=William E.|last8=Boons|first8=Geert-Jan|last9=Mariuzza|first9=Roy A.|date=2006-01-17|title=Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs)|url=https://pubmed.ncbi.nlm.nih.gov/16407132|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=103|issue=3|pages=684–689|doi=10.1073/pnas.0507656103|issn=0027-8424|pmc=1334652|pmid=16407132}}</ref> The smallest peptidoglycan fragment that binds to human PGLYRP3 is MurNAc-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), which binds with low affinity (Kd = 4.5 x 10<sup>-4</sup> M), whereas a larger fragment, MurNAc-pentapeptide (MurNAc-L-Ala-γ-D-Gln-L-Lys-D-Ala-D-Ala), binds with higher affinity (Kd = 6 x 10<sup>-6 </sup> M).<ref name=":9" /><ref name=":10" /><ref name=":11">{{Cite journal|last=Cho|first=Sangwoo|last2=Wang|first2=Qian|last3=Swaminathan|first3=Chittoor P.|last4=Hesek|first4=Dusan|last5=Lee|first5=Mijoon|last6=Boons|first6=Geert-Jan|last7=Mobashery|first7=Shahriar|last8=Mariuzza|first8=Roy A.|date=2007-05-22|title=Structural insights into the bactericidal mechanism of human peptidoglycan recognition proteins|url=https://pubmed.ncbi.nlm.nih.gov/17502600|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=104|issue=21|pages=8761–8766|doi=10.1073/pnas.0701453104|issn=0027-8424|pmc=1885576|pmid=17502600}}</ref> Human PGLYRP3, in contrast to PGLYRP1, does not bind [[Diaminopimelic acid|meso-diaminopimelic acid]] (''m''-DAP) containing fragment (MurNAc-L-Ala-γ-D-Gln-DAP-D-Ala-D-Ala).<ref name=":9" /><ref name=":10" /><ref name=":11" /> ''m''-DAP is present in the third position of peptidoglycan peptide in [[Gram-negative bacteria|Gram-negative]] bacteria and [[Gram-positive bacteria|Gram-positive]] bacilli, whereas L-[[lysine]] is in this position in peptidoglycan peptide in Gram-positive cocci. Thus, PGLYRP3 C-terminal PGRP domain has a preference for binding peptidoglycan fragments from Gram-positive cocci. Binding of MurNAc-pentapeptide induces structural rearrangements in the binding site that are essential for entry of the ligand and locks the ligand in the binding cleft.<ref>{{Cite journal|last=Guan|first=Rongjin|last2=Brown|first2=Patrick H.|last3=Swaminathan|first3=Chittoor P.|last4=Roychowdhury|first4=Abhijit|last5=Boons|first5=Geert-Jan|last6=Mariuzza|first6=Roy A.|date=May 2006|title=Crystal structure of human peptidoglycan recognition protein I alpha bound to a muramyl pentapeptide from Gram-positive bacteria|url=https://pubmed.ncbi.nlm.nih.gov/16641493|journal=Protein Science: A Publication of the Protein Society|volume=15|issue=5|pages=1199–1206|doi=10.1110/ps.062077606|issn=0961-8368|pmc=2242522|pmid=16641493}}</ref> The fine specificity of the PGLYRP3 N-terminal PGRP domain is not known.
PGLYRP3 binds peptidoglycan, a polymer of β(1-4)-linked [[N-Acetylglucosamine|''N''-acetylglucosamine]] (GlcNAc) and [[N-Acetylmuramic acid|''N''-acetylmuramic acid]] (MurNAc) cross-linked by short [[peptide]]s, the main component of [[bacteria]]l [[cell wall]].<ref name=":0" /><ref name=":2" /><ref name=":8" /><ref name=":9">{{Cite journal|last=Kumar|first=Sanjay|last2=Roychowdhury|first2=Abhijit|last3=Ember|first3=Brian|last4=Wang|first4=Qian|last5=Guan|first5=Rongjin|last6=Mariuzza|first6=Roy A.|last7=Boons|first7=Geert-Jan|date=2005-11-04|title=Selective recognition of synthetic lysine and meso-diaminopimelic acid-type peptidoglycan fragments by human peptidoglycan recognition proteins I{alpha} and S|url=https://pubmed.ncbi.nlm.nih.gov/16129677|journal=The Journal of Biological Chemistry|volume=280|issue=44|pages=37005–37012|doi=10.1074/jbc.M506385200|issn=0021-9258|pmid=16129677}}</ref><ref name=":10">{{Cite journal|last=Swaminathan|first=Chittoor P.|last2=Brown|first2=Patrick H.|last3=Roychowdhury|first3=Abhijit|last4=Wang|first4=Qian|last5=Guan|first5=Rongjin|last6=Silverman|first6=Neal|last7=Goldman|first7=William E.|last8=Boons|first8=Geert-Jan|last9=Mariuzza|first9=Roy A.|date=2006-01-17|title=Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs)|url=https://pubmed.ncbi.nlm.nih.gov/16407132|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=103|issue=3|pages=684–689|doi=10.1073/pnas.0507656103|issn=0027-8424|pmc=1334652|pmid=16407132}}</ref> The smallest peptidoglycan fragment that binds to human PGLYRP3 is MurNAc-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), which binds with low affinity (Kd = 4.5 x 10<sup>-4</sup> M), whereas a larger fragment, MurNAc-pentapeptide (MurNAc-L-Ala-γ-D-Gln-L-Lys-D-Ala-D-Ala), binds with higher affinity (Kd = 6 x 10<sup>-6 </sup> M).<ref name=":9" /><ref name=":10" /><ref name=":11">{{Cite journal|last=Cho|first=Sangwoo|last2=Wang|first2=Qian|last3=Swaminathan|first3=Chittoor P.|last4=Hesek|first4=Dusan|last5=Lee|first5=Mijoon|last6=Boons|first6=Geert-Jan|last7=Mobashery|first7=Shahriar|last8=Mariuzza|first8=Roy A.|date=2007-05-22|title=Structural insights into the bactericidal mechanism of human peptidoglycan recognition proteins|url=https://pubmed.ncbi.nlm.nih.gov/17502600|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=104|issue=21|pages=8761–8766|doi=10.1073/pnas.0701453104|issn=0027-8424|pmc=1885576|pmid=17502600}}</ref> Human PGLYRP3, in contrast to PGLYRP1, does not bind [[Diaminopimelic acid|meso-diaminopimelic acid]] (''m''-DAP) containing fragment (MurNAc-L-Ala-γ-D-Gln-DAP-D-Ala-D-Ala).<ref name=":9" /><ref name=":10" /><ref name=":11" /> ''m''-DAP is present in the third position of peptidoglycan peptide in [[Gram-negative bacteria|Gram-negative]] bacteria and [[Gram-positive bacteria|Gram-positive]] bacilli, whereas L-[[lysine]] is in this position in peptidoglycan peptide in Gram-positive cocci. Thus, PGLYRP3 C-terminal PGRP domain has a preference for binding peptidoglycan fragments from Gram-positive cocci. Binding of MurNAc-pentapeptide induces structural rearrangements in the binding site that are essential for entry of the ligand and locks the ligand in the binding cleft.<ref>{{Cite journal|last=Guan|first=Rongjin|last2=Brown|first2=Patrick H.|last3=Swaminathan|first3=Chittoor P.|last4=Roychowdhury|first4=Abhijit|last5=Boons|first5=Geert-Jan|last6=Mariuzza|first6=Roy A.|date=May 2006|title=Crystal structure of human peptidoglycan recognition protein I alpha bound to a muramyl pentapeptide from Gram-positive bacteria|url=https://pubmed.ncbi.nlm.nih.gov/16641493|journal=Protein Science: A Publication of the Protein Society|volume=15|issue=5|pages=1199–1206|doi=10.1110/ps.062077606|issn=0961-8368|pmc=2242522|pmid=16641493}}</ref> The fine specificity of the PGLYRP3 N-terminal PGRP domain is not known.


=== '''Bactericidal activity''' ===
=== Bactericidal activity ===
Human PGLYRP3 is directly bactericidal for both Gram-positive (''[[Bacillus subtilis]]'', ''[[Bacillus licheniformis]]'', ''[[Bacillus cereus]]'', ''[[Lactobacillus acidophilus]]'', ''[[Listeria monocytogenes]]'', ''[[Staphylococcus aureus]]'', ''[[Streptococcus pyogenes]]'') and Gram-negative (''[[Escherichia coli]]'', ''[[Proteus vulgaris]]'', ''[[Salmonella enterica]]'', ''[[Shigella sonnei]]'', ''[[Pseudomonas aeruginosa]]'') bacteria.<ref name=":2" /><ref name=":12">{{Cite journal|last=Wang|first=Minhui|last2=Liu|first2=Li-Hui|last3=Wang|first3=Shiyong|last4=Li|first4=Xinna|last5=Lu|first5=Xiaofeng|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2007-03-01|title=Human peptidoglycan recognition proteins require zinc to kill both gram-positive and gram-negative bacteria and are synergistic with antibacterial peptides|url=https://pubmed.ncbi.nlm.nih.gov/17312159|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=178|issue=5|pages=3116–3125|doi=10.4049/jimmunol.178.5.3116|issn=0022-1767|pmid=17312159}}</ref><ref name=":13">{{Cite journal|last=Kashyap|first=Des Raj|last2=Wang|first2=Minhui|last3=Liu|first3=Li-Hui|last4=Boons|first4=Geert-Jan|last5=Gupta|first5=Dipika|last6=Dziarski|first6=Roman|date=June 2011|title=Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems|url=https://pubmed.ncbi.nlm.nih.gov/21602801|journal=Nature Medicine|volume=17|issue=6|pages=676–683|doi=10.1038/nm.2357|issn=1546-170X|pmc=3176504|pmid=21602801}}</ref><ref name=":14">{{Cite journal|last=Kashyap|first=Des Raj|last2=Rompca|first2=Annemarie|last3=Gaballa|first3=Ahmed|last4=Helmann|first4=John D.|last5=Chan|first5=Jefferson|last6=Chang|first6=Christopher J.|last7=Hozo|first7=Iztok|last8=Gupta|first8=Dipika|last9=Dziarski|first9=Roman|date=July 2014|title=Peptidoglycan recognition proteins kill bacteria by inducing oxidative, thiol, and metal stress|url=https://pubmed.ncbi.nlm.nih.gov/25032698|journal=PLoS pathogens|volume=10|issue=7|pages=e1004280|doi=10.1371/journal.ppat.1004280|issn=1553-7374|pmc=4102600|pmid=25032698}}</ref>
Human PGLYRP3 is directly bactericidal for both Gram-positive (''[[Bacillus subtilis]]'', ''[[Bacillus licheniformis]]'', ''[[Bacillus cereus]]'', ''[[Lactobacillus acidophilus]]'', ''[[Listeria monocytogenes]]'', ''[[Staphylococcus aureus]]'', ''[[Streptococcus pyogenes]]'') and Gram-negative (''[[Escherichia coli]]'', ''[[Proteus vulgaris]]'', ''[[Salmonella enterica]]'', ''[[Shigella sonnei]]'', ''[[Pseudomonas aeruginosa]]'') bacteria.<ref name=":2" /><ref name=":12">{{Cite journal|last=Wang|first=Minhui|last2=Liu|first2=Li-Hui|last3=Wang|first3=Shiyong|last4=Li|first4=Xinna|last5=Lu|first5=Xiaofeng|last6=Gupta|first6=Dipika|last7=Dziarski|first7=Roman|date=2007-03-01|title=Human peptidoglycan recognition proteins require zinc to kill both gram-positive and gram-negative bacteria and are synergistic with antibacterial peptides|url=https://pubmed.ncbi.nlm.nih.gov/17312159|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=178|issue=5|pages=3116–3125|doi=10.4049/jimmunol.178.5.3116|issn=0022-1767|pmid=17312159}}</ref><ref name=":13">{{Cite journal|last=Kashyap|first=Des Raj|last2=Wang|first2=Minhui|last3=Liu|first3=Li-Hui|last4=Boons|first4=Geert-Jan|last5=Gupta|first5=Dipika|last6=Dziarski|first6=Roman|date=June 2011|title=Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems|url=https://pubmed.ncbi.nlm.nih.gov/21602801|journal=Nature Medicine|volume=17|issue=6|pages=676–683|doi=10.1038/nm.2357|issn=1546-170X|pmc=3176504|pmid=21602801}}</ref><ref name=":14">{{Cite journal|last=Kashyap|first=Des Raj|last2=Rompca|first2=Annemarie|last3=Gaballa|first3=Ahmed|last4=Helmann|first4=John D.|last5=Chan|first5=Jefferson|last6=Chang|first6=Christopher J.|last7=Hozo|first7=Iztok|last8=Gupta|first8=Dipika|last9=Dziarski|first9=Roman|date=July 2014|title=Peptidoglycan recognition proteins kill bacteria by inducing oxidative, thiol, and metal stress|url=https://pubmed.ncbi.nlm.nih.gov/25032698|journal=PLoS pathogens|volume=10|issue=7|pages=e1004280|doi=10.1371/journal.ppat.1004280|issn=1553-7374|pmc=4102600|pmid=25032698}}</ref>


The mechanism of bacterial killing by PGLYRP3 is based on induction of lethal envelope stress, which eventually leads to the shutdown of [[Transcription (biology)|transcription]] and [[Translation (biology)|translation]].<ref name=":13" /> PGLYRP3-induced killing involves simultaneous induction of three stress responses in both Gram-positive and Gram-negative bacteria: oxidative stress due to production of [[reactive oxygen species]] ([[hydrogen peroxide]] and [[Hydroxyl radical|hydroxyl radicals]]), [[thiol]] stress due to depletion ([[Redox|oxidation]]) of cellular thiols, and metal stress due to an increase in intracellular free (labile) metal ions.<ref name=":13" /><ref name=":14" /> PGLYRP3-induced bacterial killing does not involve cell membrane permeabilization, which is typical for [[Defensin|defensins]] and other [[antimicrobial peptides]], cell wall hydrolysis, or [[osmotic shock]].<ref name=":2" /><ref name=":12" /><ref name=":13" /> Human PGLYRP3 has synergistic bactericidal activity with antibacterial peptides.<ref name=":12" />
The mechanism of bacterial killing by PGLYRP3 is based on induction of lethal envelope stress, which eventually leads to the shutdown of [[Transcription (biology)|transcription]] and [[Translation (biology)|translation]].<ref name=":13" /> PGLYRP3-induced killing involves simultaneous induction of three stress responses in both Gram-positive and Gram-negative bacteria: oxidative stress due to production of [[reactive oxygen species]] ([[hydrogen peroxide]] and [[hydroxyl radical]]s), [[thiol]] stress due to depletion ([[Redox|oxidation]]) of cellular thiols, and metal stress due to an increase in intracellular free (labile) metal ions.<ref name=":13" /><ref name=":14" /> PGLYRP3-induced bacterial killing does not involve cell membrane permeabilization, which is typical for [[defensin]]s and other [[antimicrobial peptides]], cell wall hydrolysis, or [[osmotic shock]].<ref name=":2" /><ref name=":12" /><ref name=":13" /> Human PGLYRP3 has synergistic bactericidal activity with antibacterial peptides.<ref name=":12" />


=== '''Defense against infections''' ===
=== Defense against infections ===
PGLYRP3 plays a limited role in host defense against [[Infection|infections]]. [[Nasal administration|Intranasal]] administration of PGLYRP3 protects mice from lung infection with ''S. aureus'' and ''E. coli'',<ref name=":2" /><ref>{{Cite journal|last=Dziarski|first=Roman|last2=Kashyap|first2=Des Raj|last3=Gupta|first3=Dipika|date=June 2012|title=Mammalian peptidoglycan recognition proteins kill bacteria by activating two-component systems and modulate microbiome and inflammation|url=https://pubmed.ncbi.nlm.nih.gov/22432705|journal=Microbial Drug Resistance (Larchmont, N.Y.)|volume=18|issue=3|pages=280–285|doi=10.1089/mdr.2012.0002|issn=1931-8448|pmc=3412580|pmid=22432705}}</ref> but ''PGLYRP3''-deficient mice do not have altered sensitivity to ''[[Streptococcus pneumoniae]]''-induced [[pneumonia]].<ref>{{Cite journal|last=Shrivastav|first=Anshu|last2=Dabrowski|first2=Alexander N.|last3=Conrad|first3=Claudia|last4=Baal|first4=Nelli|last5=Hackstein|first5=Holger|last6=Plog|first6=Stephanie|last7=Dietert|first7=Kristina|last8=Gruber|first8=Achim D.|last9=N'Guessan|first9=Philippe D.|last10=Aly|first10=Sahar|last11=Suttorp|first11=Norbert|date=2018|title=Peptidoglycan Recognition Protein 3 Does Not Alter the Outcome of Pneumococcal Pneumonia in Mice|url=https://pubmed.ncbi.nlm.nih.gov/29449834|journal=Frontiers in Microbiology|volume=9|pages=103|doi=10.3389/fmicb.2018.00103|issn=1664-302X|pmc=5799233|pmid=29449834}}</ref>
PGLYRP3 plays a limited role in host defense against [[infection]]s. [[Nasal administration|Intranasal]] administration of PGLYRP3 protects mice from lung infection with ''S. aureus'' and ''E. coli'',<ref name=":2" /><ref>{{Cite journal|last=Dziarski|first=Roman|last2=Kashyap|first2=Des Raj|last3=Gupta|first3=Dipika|date=June 2012|title=Mammalian peptidoglycan recognition proteins kill bacteria by activating two-component systems and modulate microbiome and inflammation|url=https://pubmed.ncbi.nlm.nih.gov/22432705|journal=Microbial Drug Resistance (Larchmont, N.Y.)|volume=18|issue=3|pages=280–285|doi=10.1089/mdr.2012.0002|issn=1931-8448|pmc=3412580|pmid=22432705}}</ref> but ''PGLYRP3''-deficient mice do not have altered sensitivity to ''[[Streptococcus pneumoniae]]''-induced [[pneumonia]].<ref>{{Cite journal|last=Shrivastav|first=Anshu|last2=Dabrowski|first2=Alexander N.|last3=Conrad|first3=Claudia|last4=Baal|first4=Nelli|last5=Hackstein|first5=Holger|last6=Plog|first6=Stephanie|last7=Dietert|first7=Kristina|last8=Gruber|first8=Achim D.|last9=N'Guessan|first9=Philippe D.|last10=Aly|first10=Sahar|last11=Suttorp|first11=Norbert|date=2018|title=Peptidoglycan Recognition Protein 3 Does Not Alter the Outcome of Pneumococcal Pneumonia in Mice|url=https://pubmed.ncbi.nlm.nih.gov/29449834|journal=Frontiers in Microbiology|volume=9|pages=103|doi=10.3389/fmicb.2018.00103|issn=1664-302X|pmc=5799233|pmid=29449834}}</ref>


=== '''Maintaining microbiome''' ===
=== Maintaining microbiome ===
Mouse PGLYRP3 plays a role in maintaining healthy [[microbiome]], as ''PGLYRP3''-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to [[colitis]].<ref name=":3" /><ref name=":15">{{Cite journal|last=Dziarski|first=Roman|last2=Park|first2=Shin Yong|last3=Kashyap|first3=Des Raj|last4=Dowd|first4=Scot E.|last5=Gupta|first5=Dipika|date=2016|title=Pglyrp-Regulated Gut Microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii Enhance and Alistipes finegoldii Attenuates Colitis in Mice|url=https://pubmed.ncbi.nlm.nih.gov/26727498|journal=PloS One|volume=11|issue=1|pages=e0146162|doi=10.1371/journal.pone.0146162|issn=1932-6203|pmc=4699708|pmid=26727498}}</ref><ref name=":16">{{Cite journal|last=Jing|first=Xuefang|last2=Zulfiqar|first2=Fareeha|last3=Park|first3=Shin Yong|last4=Núñez|first4=Gabriel|last5=Dziarski|first5=Roman|last6=Gupta|first6=Dipika|date=2014-09-15|title=Peptidoglycan recognition protein 3 and Nod2 synergistically protect mice from dextran sodium sulfate-induced colitis|url=https://pubmed.ncbi.nlm.nih.gov/25114103|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=193|issue=6|pages=3055–3069|doi=10.4049/jimmunol.1301548|issn=1550-6606|pmc=4157132|pmid=25114103}}</ref>
Mouse PGLYRP3 plays a role in maintaining healthy [[microbiome]], as ''PGLYRP3''-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to [[colitis]].<ref name=":3" /><ref name=":15">{{Cite journal|last=Dziarski|first=Roman|last2=Park|first2=Shin Yong|last3=Kashyap|first3=Des Raj|last4=Dowd|first4=Scot E.|last5=Gupta|first5=Dipika|date=2016|title=Pglyrp-Regulated Gut Microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii Enhance and Alistipes finegoldii Attenuates Colitis in Mice|url=https://pubmed.ncbi.nlm.nih.gov/26727498|journal=PloS One|volume=11|issue=1|pages=e0146162|doi=10.1371/journal.pone.0146162|issn=1932-6203|pmc=4699708|pmid=26727498}}</ref><ref name=":16">{{Cite journal|last=Jing|first=Xuefang|last2=Zulfiqar|first2=Fareeha|last3=Park|first3=Shin Yong|last4=Núñez|first4=Gabriel|last5=Dziarski|first5=Roman|last6=Gupta|first6=Dipika|date=2014-09-15|title=Peptidoglycan recognition protein 3 and Nod2 synergistically protect mice from dextran sodium sulfate-induced colitis|url=https://pubmed.ncbi.nlm.nih.gov/25114103|journal=Journal of Immunology (Baltimore, Md.: 1950)|volume=193|issue=6|pages=3055–3069|doi=10.4049/jimmunol.1301548|issn=1550-6606|pmc=4157132|pmid=25114103}}</ref>


=== '''Effects on inflammation''' ===
=== Effects on inflammation ===
Mouse PGLYRP3 plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine and skin. ''PGLYRP3''-deficient mice are more sensitive than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP3 protects mice from DSS-induced colitis.<ref name=":3" /><ref name=":16" /> The anti-inflammatory effect of PGLYRP3 on DSS-induced colitis depends on the PGLYRP3-regulated intestinal microbiome, because this greater sensitivity of ''PGLYRP3''-deficient mice to DSS-induced colitis could be transferred to wild type [[Germ-free animal|germ-free]] mice or to antibiotic-treated mice by microbiome transplant from ''PGLYRP3''-deficient mice<ref name=":3" /><ref name=":16" /> or by ''PGLYRP3''-regulated bacteria.<ref name=":15" /> PGLYRP3 is also directly anti-inflammatory in [[Gastrointestinal tract|intestinal]] [[Epithelium|epithelial cells]].<ref>{{Cite journal|last=Zenhom|first=Marwa|last2=Hyder|first2=Ayman|last3=Kraus-Stojanowic|first3=Ina|last4=Auinger|first4=Annegret|last5=Roeder|first5=Thomas|last6=Schrezenmeir|first6=Jürgen|date=June 2011|title=PPARγ-dependent peptidoglycan recognition protein 3 (PGlyRP3) expression regulates proinflammatory cytokines by microbial and dietary fatty acids|url=https://pubmed.ncbi.nlm.nih.gov/21176858|journal=Immunobiology|volume=216|issue=6|pages=715–724|doi=10.1016/j.imbio.2010.10.008|issn=1878-3279|pmid=21176858}}</ref><ref>{{Cite journal|last=Zenhom|first=Marwa|last2=Hyder|first2=Ayman|last3=de Vrese|first3=Michael|last4=Heller|first4=Knut J.|last5=Roeder|first5=Thomas|last6=Schrezenmeir|first6=Jürgen|date=April 2012|title=Peptidoglycan recognition protein 3 (PglyRP3) has an anti-inflammatory role in intestinal epithelial cells|url=https://pubmed.ncbi.nlm.nih.gov/22099350|journal=Immunobiology|volume=217|issue=4|pages=412–419|doi=10.1016/j.imbio.2011.10.013|issn=1878-3279|pmid=22099350}}</ref><ref>{{Cite journal|last=Zenhom|first=Marwa|last2=Hyder|first2=Ayman|last3=de Vrese|first3=Michael|last4=Heller|first4=Knut J.|last5=Roeder|first5=Thomas|last6=Schrezenmeir|first6=Jürgen|date=May 2011|title=Prebiotic oligosaccharides reduce proinflammatory cytokines in intestinal Caco-2 cells via activation of PPARγ and peptidoglycan recognition protein 3|url=https://pubmed.ncbi.nlm.nih.gov/21451128|journal=The Journal of Nutrition|volume=141|issue=5|pages=971–977|doi=10.3945/jn.110.136176|issn=1541-6100|pmid=21451128}}</ref>
Mouse PGLYRP3 plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine and skin. ''PGLYRP3''-deficient mice are more sensitive than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP3 protects mice from DSS-induced colitis.<ref name=":3" /><ref name=":16" /> The anti-inflammatory effect of PGLYRP3 on DSS-induced colitis depends on the PGLYRP3-regulated intestinal microbiome, because this greater sensitivity of ''PGLYRP3''-deficient mice to DSS-induced colitis could be transferred to wild type [[Germ-free animal|germ-free]] mice or to antibiotic-treated mice by microbiome transplant from ''PGLYRP3''-deficient mice<ref name=":3" /><ref name=":16" /> or by ''PGLYRP3''-regulated bacteria.<ref name=":15" /> PGLYRP3 is also directly anti-inflammatory in [[Gastrointestinal tract|intestinal]] [[Epithelium|epithelial cells]].<ref>{{Cite journal|last=Zenhom|first=Marwa|last2=Hyder|first2=Ayman|last3=Kraus-Stojanowic|first3=Ina|last4=Auinger|first4=Annegret|last5=Roeder|first5=Thomas|last6=Schrezenmeir|first6=Jürgen|date=June 2011|title=PPARγ-dependent peptidoglycan recognition protein 3 (PGlyRP3) expression regulates proinflammatory cytokines by microbial and dietary fatty acids|url=https://pubmed.ncbi.nlm.nih.gov/21176858|journal=Immunobiology|volume=216|issue=6|pages=715–724|doi=10.1016/j.imbio.2010.10.008|issn=1878-3279|pmid=21176858}}</ref><ref>{{Cite journal|last=Zenhom|first=Marwa|last2=Hyder|first2=Ayman|last3=de Vrese|first3=Michael|last4=Heller|first4=Knut J.|last5=Roeder|first5=Thomas|last6=Schrezenmeir|first6=Jürgen|date=April 2012|title=Peptidoglycan recognition protein 3 (PglyRP3) has an anti-inflammatory role in intestinal epithelial cells|url=https://pubmed.ncbi.nlm.nih.gov/22099350|journal=Immunobiology|volume=217|issue=4|pages=412–419|doi=10.1016/j.imbio.2011.10.013|issn=1878-3279|pmid=22099350}}</ref><ref>{{Cite journal|last=Zenhom|first=Marwa|last2=Hyder|first2=Ayman|last3=de Vrese|first3=Michael|last4=Heller|first4=Knut J.|last5=Roeder|first5=Thomas|last6=Schrezenmeir|first6=Jürgen|date=May 2011|title=Prebiotic oligosaccharides reduce proinflammatory cytokines in intestinal Caco-2 cells via activation of PPARγ and peptidoglycan recognition protein 3|url=https://pubmed.ncbi.nlm.nih.gov/21451128|journal=The Journal of Nutrition|volume=141|issue=5|pages=971–977|doi=10.3945/jn.110.136176|issn=1541-6100|pmid=21451128}}</ref>


Line 52: Line 52:
* [[Peptidoglycan]]
* [[Peptidoglycan]]
* [[Innate immune system]]
* [[Innate immune system]]
* [[Cell wall#Bacterial%20cell%20walls|Bacterial cell walls]]
* [[Cell wall#Bacterial cell walls|Bacterial cell walls]]


== References ==
== References ==
<references />
<references />

== Further reading ==
== Further reading ==
Dziarski R, Royet J, Gupta D. Peptidoglycan Recognition Proteins and Lysozyme.  In: Encyclopedia of Immunobiology, 2016. vol. 2, pp. 389-403, Ratcliffe MJH (ed), Elsevier Ltd., ISBN-13: 978-0123742797. <nowiki>http://dx.doi.org/10.1016/B978-0-12-374279-7.02022-1</nowiki>
* Dziarski R, Royet J, Gupta D. Peptidoglycan Recognition Proteins and Lysozyme.  In: Encyclopedia of Immunobiology, 2016. vol. 2, pp. 389-403, Ratcliffe MJH (ed), Elsevier Ltd., {{ISBN|978-0123742797}}. {{doi|10.1016/B978-0-12-374279-7.02022-1}}

Royet J, Gupta D, Dziarski R. Peptidoglycan recognition proteins: modulators of the microbiome and inflammation. Nat Rev Immunol. 2011 Nov 11;11(12):837-51. doi: 10.1038/nri3089. PMID: 22076558

⚫
Royet J, Dziarski R. Peptidoglycan Recognition Proteins: pleiotropic sensors and effectors of antimicrobial defenses.  Nat Rev Microbiol. 2007 Apr;5(4):264-77. doi: 10.1038/nrmicro1620. PMID: 17363965


Dziarski R, Gupta D. The peptidoglycan recognition proteins (PGRPs). Genome Biol. 2006;7(8):232. doi: 10.1186/gb-2006-7-8-232. PMID: 16930467
* Royet J, Gupta D, Dziarski R. Peptidoglycan recognition proteins: modulators of the microbiome and inflammation. Nat Rev Immunol. 2011 Nov 11;11(12):837-51. {{doi|10.1038/nri3089}}. PMID 22076558


⚫
* Royet J, Dziarski R. Peptidoglycan Recognition Proteins: pleiotropic sensors and effectors of antimicrobial defenses.  Nat Rev Microbiol. 2007 Apr;5(4):264-77. {{doi|10.1038/nrmicro1620}}. PMID 17363965
⚫
Bastos PAD, Wheeler R, Boneca IG. Uptake, recognition and responses to peptidoglycan in the mammalian host. FEMS Microbiol Rev. 2020 Sep 8:fuaa044. doi: 10.1093/femsre/fuaa044. Online ahead of print. PMID: 32897324


Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol. 2018 Apr;18(4):243-254. doi: 10.1038/nri.2017.136. Epub 2018 Jan 2. PMID: 29292393
* Dziarski R, Gupta D. The peptidoglycan recognition proteins (PGRPs). Genome Biol. 2006;7(8):232. {{doi|10.1186/gb-2006-7-8-232}}. PMID 16930467


⚫
* Bastos PAD, Wheeler R, Boneca IG. Uptake, recognition and responses to peptidoglycan in the mammalian host. FEMS Microbiol Rev. 2020 Sep 8:fuaa044. {{doi|10.1093/femsre/fuaa044}}. Online ahead of print. PMID 32897324
⚫
Laman JD, 't Hart BA, Power C, Dziarski R. Bacterial Peptidoglycan as a Driver of Chronic Brain Inflammation. Trends Mol Med. 2020 Jul;26(7):670-682. doi: 10.1016/j.molmed.2019.11.006. Epub 2020 Feb 21. PMID: 32589935


Gonzalez-Santana A, Diaz Heijtz R. Bacterial Peptidoglycans from Microbiota in Neurodevelopment and Behavior. Trends Mol Med. 2020 Aug;26(8):729-743. doi: 10.1016/j.molmed.2020.05.003. Epub 2020 Jun 5. PMID: 32507655
* Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol. 2018 Apr;18(4):243-254. {{doi|10.1038/nri.2017.136}}. Epub 2018 Jan 2. PMID 29292393


⚫
* Laman JD, 't Hart BA, Power C, Dziarski R. Bacterial Peptidoglycan as a Driver of Chronic Brain Inflammation. Trends Mol Med. 2020 Jul;26(7):670-682. {{doi|10.1016/j.molmed.2019.11.006}}. Epub 2020 Feb 21. PMID 32589935


* Gonzalez-Santana A, Diaz Heijtz R. Bacterial Peptidoglycans from Microbiota in Neurodevelopment and Behavior. Trends Mol Med. 2020 Aug;26(8):729-743. {{doi|10.1016/j.molmed.2020.05.003}}. Epub 2020 Jun 5. PMID 32507655


[[Category:Proteins]]
[[Category:Proteins]]

Revision as of 12:22, 5 November 2020

PGLYRP3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPGLYRP3, PGRP-Ialpha, PGRPIA, PGLYRPIalpha, peptidoglycan recognition protein 3
External IDsOMIM: 608197; MGI: 2685266; HomoloGene: 71559; GeneCards: PGLYRP3; OMA:PGLYRP3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

114771

242100

Ensembl

ENSG00000159527

ENSMUSG00000042244

UniProt

Q96LB9

A1A547

RefSeq (mRNA)

NM_052891

NM_207247

RefSeq (protein)

NP_443123

NP_997130

Location (UCSC)Chr 1: 153.3 – 153.31 MbChr 3: 91.92 – 91.94 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Human PGLYRP3 gene, cDNA, and protein

Peptidoglycan recognition protein 3 (PGLYRP3, formerly PGRP-Iα) is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP3 gene.[5][6][7]

Discovery

PGLYRP3 (formerly PGRP-Iα), a member of a family of human Peptidoglycan Recognition Proteins (PGRPs), was discovered in 2001 by Roman Dziarski and coworkers who cloned and identified the genes for three human PGRPs, named PGRP-L, PGRP-Iα, and PGRP-Iβ (named for long and intermediate size transcripts),[5] and established that human genome codes for a family of 4 PGRPs: PGRP-S (short PGRP or PGRP-S)[8] and PGRP-L, PGRP-Iα, and PGRP-Iβ.[5] Subsequently, the Human Genome Organization Gene Nomenclature Committee changed the gene symbols of PGRP-S, PGRP-L, PGRP-Iα, and PGRP-Iβ to PGLYRP1 (peptidoglycan recognition protein 1), PGLYRP2 (peptidoglycan recognition protein 2), PGLYRP3 (peptidoglycan recognition protein 3), and PGLYRP4 (peptidoglycan recognition protein 4), respectively, and this nomenclature is currently also used for other mammalian PGRPs.

Tissue distribution and secretion

PGLYRP3 has similar expression to PGLYRP4 (peptidoglycan recognition protein 4) but not identical.[5][9] PGLYRP3 is constitutively expressed in the skin, in the eye, and in the mucous membranes in the tongue, throat, and esophagus, and at a much lower level in the remaining parts of the intestinal tract.[5][9][10][11] Bacteria and their products increase the expression of PGLYRP3 in keratinocytes and oral epithelial cells.[7][12] Mouse PGLYRP3 is also differentially expressed in the developing brain and this expression is influenced by the intestinal microbiome.[13] PGLYRP3 is secreted and forms disulfide-linked dimers.[9]

Structure

PGLYRP3, similar to PGLYRP4, has two peptidoglycan-binding type 2 amidase domains (also known as PGRP domains), which are not identical (have 38% amino acid identity in humans)[5][14] and do not have amidase enzymatic activity.[15] PGLYRP3 is secreted, it is glycosylated, and its glycosylation is required for its bactericidal activity.[9] PGLYRP3 forms disulfide-linked homodimers, but when expressed in the same cells with PGLYRP4, it forms PGLYRP3:PGLYRP4 disulfide-linked heterodimers.[9]

The C-terminal peptidoglycan-binding domain of human PGLYRP3 has been crystallized and its structure solved[16] and is similar to human PGLYRP1.[17] PGLYRP3 C-terminal PGRP domain contains a central β-sheet composed of five β-strands and three α-helices and N-terminal segment unique to PGRPs and not found in bacteriophage and prokaryotic amidases.[16]

Human PGLYRP3 C-terminal PGRP domain, similar to PGLYRP1,[17] has three pairs of cysteines, which form three disulfide bonds at positions 178–300, 194–238, and 214–220.[16] The Cys214–Cys220 disulfide is broadly conserved in invertebrate and vertebrate PRGPs, the Cys178–Cys300 disulfide is conserved in all mammalian PGRPs, and the Cys194–238 disulfide is unique to mammalian PGLYRP1, PGLYRP3, and PGLYRP4, but not found in the amidase-active PGLYRP2.[5][15][16][17] The structures of the entire PGLYRP3 molecule (with two PGRP domains) and of the disulfide-linked dimer are unknown.

PGLYRP3 C-terminal PGRP domain contains peptidoglycan-binding site, which is a long cleft whose walls are formed by α-helix and five β-loops and the floor by a β-sheet. This site binds muramyl-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), but can also accommodate larger peptidoglycan fragments, such as disaccharide-pentapeptide.[18] Located opposite the peptidoglycan-binding cleft is a large hydrophobic groove, formed by residues 177–198 (the PGRP-specific segment).[18]

Functions

The PGLYRP3 protein plays an important role in the innate immune responses.

Peptidoglycan binding

PGLYRP3 binds peptidoglycan, a polymer of β(1-4)-linked N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) cross-linked by short peptides, the main component of bacterial cell wall.[5][9][18][19][20] The smallest peptidoglycan fragment that binds to human PGLYRP3 is MurNAc-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), which binds with low affinity (Kd = 4.5 x 10-4 M), whereas a larger fragment, MurNAc-pentapeptide (MurNAc-L-Ala-γ-D-Gln-L-Lys-D-Ala-D-Ala), binds with higher affinity (Kd = 6 x 10-6  M).[19][20][21] Human PGLYRP3, in contrast to PGLYRP1, does not bind meso-diaminopimelic acid (m-DAP) containing fragment (MurNAc-L-Ala-γ-D-Gln-DAP-D-Ala-D-Ala).[19][20][21] m-DAP is present in the third position of peptidoglycan peptide in Gram-negative bacteria and Gram-positive bacilli, whereas L-lysine is in this position in peptidoglycan peptide in Gram-positive cocci. Thus, PGLYRP3 C-terminal PGRP domain has a preference for binding peptidoglycan fragments from Gram-positive cocci. Binding of MurNAc-pentapeptide induces structural rearrangements in the binding site that are essential for entry of the ligand and locks the ligand in the binding cleft.[22] The fine specificity of the PGLYRP3 N-terminal PGRP domain is not known.

Bactericidal activity

Human PGLYRP3 is directly bactericidal for both Gram-positive (Bacillus subtilis, Bacillus licheniformis, Bacillus cereus, Lactobacillus acidophilus, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pyogenes) and Gram-negative (Escherichia coli, Proteus vulgaris, Salmonella enterica, Shigella sonnei, Pseudomonas aeruginosa) bacteria.[9][23][24][25]

The mechanism of bacterial killing by PGLYRP3 is based on induction of lethal envelope stress, which eventually leads to the shutdown of transcription and translation.[24] PGLYRP3-induced killing involves simultaneous induction of three stress responses in both Gram-positive and Gram-negative bacteria: oxidative stress due to production of reactive oxygen species (hydrogen peroxide and hydroxyl radicals), thiol stress due to depletion (oxidation) of cellular thiols, and metal stress due to an increase in intracellular free (labile) metal ions.[24][25] PGLYRP3-induced bacterial killing does not involve cell membrane permeabilization, which is typical for defensins and other antimicrobial peptides, cell wall hydrolysis, or osmotic shock.[9][23][24] Human PGLYRP3 has synergistic bactericidal activity with antibacterial peptides.[23]

Defense against infections

PGLYRP3 plays a limited role in host defense against infections. Intranasal administration of PGLYRP3 protects mice from lung infection with S. aureus and E. coli,[9][26] but PGLYRP3-deficient mice do not have altered sensitivity to Streptococcus pneumoniae-induced pneumonia.[27]

Maintaining microbiome

Mouse PGLYRP3 plays a role in maintaining healthy microbiome, as PGLYRP3-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to colitis.[11][28][29]

Effects on inflammation

Mouse PGLYRP3 plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine and skin. PGLYRP3-deficient mice are more sensitive than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP3 protects mice from DSS-induced colitis.[11][29] The anti-inflammatory effect of PGLYRP3 on DSS-induced colitis depends on the PGLYRP3-regulated intestinal microbiome, because this greater sensitivity of PGLYRP3-deficient mice to DSS-induced colitis could be transferred to wild type germ-free mice or to antibiotic-treated mice by microbiome transplant from PGLYRP3-deficient mice[11][29] or by PGLYRP3-regulated bacteria.[28] PGLYRP3 is also directly anti-inflammatory in intestinal epithelial cells.[30][31][32]

PGLYRP3-deficient mice are more sensitive than wild type mice to experimentally induced atopic dermatitis.[33] These results indicate that mouse PGLYRP3 is anti-inflammatory and protects skin from inflammation. This anti-inflammatory effect is due to decreased numbers and activity of T helper 17 (Th17) cells and increased numbers of T regulatory (Treg) cells.[33]

Medical relevance

Genetic PGLYRP3 variants are associated with some diseases. Patients with inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, have significantly more frequent missense variants in PGLYRP3 gene (and also in the other three PGLYRP genes) than healthy controls.[14] PGLYRP3 variants are also associated with Parkinson’s disease[34] and psoriasis.[35][36] These results suggest that PGLYRP3 protects humans from these diseases, and that mutations in PGLYRP3 gene are among the genetic factors predisposing to these diseases. PGLYRP3 variants are also associated with the composition of airway microbiome.[37]

See also

References

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Further reading

  • Royet J, Gupta D, Dziarski R. Peptidoglycan recognition proteins: modulators of the microbiome and inflammation. Nat Rev Immunol. 2011 Nov 11;11(12):837-51. doi:10.1038/nri3089. PMID 22076558
  • Royet J, Dziarski R. Peptidoglycan Recognition Proteins: pleiotropic sensors and effectors of antimicrobial defenses.  Nat Rev Microbiol. 2007 Apr;5(4):264-77. doi:10.1038/nrmicro1620. PMID 17363965
  • Dziarski R, Gupta D. The peptidoglycan recognition proteins (PGRPs). Genome Biol. 2006;7(8):232. doi:10.1186/gb-2006-7-8-232. PMID 16930467
  • Bastos PAD, Wheeler R, Boneca IG. Uptake, recognition and responses to peptidoglycan in the mammalian host. FEMS Microbiol Rev. 2020 Sep 8:fuaa044. doi:10.1093/femsre/fuaa044. Online ahead of print. PMID 32897324
  • Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol. 2018 Apr;18(4):243-254. doi:10.1038/nri.2017.136. Epub 2018 Jan 2. PMID 29292393
  • Laman JD, 't Hart BA, Power C, Dziarski R. Bacterial Peptidoglycan as a Driver of Chronic Brain Inflammation. Trends Mol Med. 2020 Jul;26(7):670-682. doi:10.1016/j.molmed.2019.11.006. Epub 2020 Feb 21. PMID 32589935
  • Gonzalez-Santana A, Diaz Heijtz R. Bacterial Peptidoglycans from Microbiota in Neurodevelopment and Behavior. Trends Mol Med. 2020 Aug;26(8):729-743. doi:10.1016/j.molmed.2020.05.003. Epub 2020 Jun 5. PMID 32507655
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