| Structural highlights
5w7f is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.8Å |
| Ligands: | CA, DAO, FTT, GCS, NAG |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
AOAH_MOUSE Removes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides (LPS) (PubMed:12810692, PubMed:15155618, PubMed:17322564, PubMed:19860560). By breaking down LPS, terminates the host response to bacterial infection and prevents prolonged and damaging inflammatory responses (PubMed:17322564, PubMed:19860560, PubMed:28622363). In peritoneal macrophages, seems to be important for recovery from a state of immune tolerance following infection by Gram-negative bacteria (PubMed:18779055).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
LPS is a potent bacterial endotoxin that triggers the innate immune system. Proper recognition of LPS by pattern-recognition receptors requires a full complement of typically six acyl chains in the lipid portion. Acyloxyacyl hydrolase (AOAH) is a host enzyme that removes secondary (acyloxyacyl-linked) fatty acids from LPS, rendering it immunologically inert. This activity is critical for recovery from immune tolerance that follows Gram-negative infection. To understand the molecular mechanism of AOAH function, we determined its crystal structure and its complex with LPS. The substrate's lipid moiety is accommodated in a large hydrophobic pocket formed by the saposin and catalytic domains with a secondary acyl chain inserted into a narrow lateral hydrophobic tunnel at the active site. The enzyme establishes dispensable contacts with the phosphate groups of LPS but does not interact with its oligosaccharide portion. Proteolytic processing allows movement of an amphipathic helix possibly involved in substrate access at membranes.
Crystal structure of the mammalian lipopolysaccharide detoxifier.,Gorelik A, Illes K, Nagar B Proc Natl Acad Sci U S A. 2018 Jan 17. pii: 1719834115. doi:, 10.1073/pnas.1719834115. PMID:29343645[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lu M, Zhang M, Kitchens RL, Fosmire S, Takashima A, Munford RS. Stimulus-dependent deacylation of bacterial lipopolysaccharide by dendritic cells. J Exp Med. 2003 Jun 16;197(12):1745-54. doi: 10.1084/jem.20030420. PMID:12810692 doi:https://dx.doi.org/10.1084/jem.20030420
- ↑ Feulner JA, Lu M, Shelton JM, Zhang M, Richardson JA, Munford RS. Identification of acyloxyacyl hydrolase, a lipopolysaccharide-detoxifying enzyme, in the murine urinary tract. Infect Immun. 2004 Jun;72(6):3171-8. doi: 10.1128/IAI.72.6.3171-3178.2004. PMID:15155618 doi:https://dx.doi.org/10.1128/IAI.72.6.3171-3178.2004
- ↑ Shao B, Lu M, Katz SC, Varley AW, Hardwick J, Rogers TE, Ojogun N, Rockey DC, Dematteo RP, Munford RS. A host lipase detoxifies bacterial lipopolysaccharides in the liver and spleen. J Biol Chem. 2007 May 4;282(18):13726-35. doi: 10.1074/jbc.M609462200. Epub 2007 , Feb 24. PMID:17322564 doi:https://dx.doi.org/10.1074/jbc.M609462200
- ↑ Lu M, Varley AW, Ohta S, Hardwick J, Munford RS. Host inactivation of bacterial lipopolysaccharide prevents prolonged tolerance following gram-negative bacterial infection. Cell Host Microbe. 2008 Sep 11;4(3):293-302. doi: 10.1016/j.chom.2008.06.009. PMID:18779055 doi:https://dx.doi.org/10.1016/j.chom.2008.06.009
- ↑ Ojogun N, Kuang TY, Shao B, Greaves DR, Munford RS, Varley AW. Overproduction of acyloxyacyl hydrolase by macrophages and dendritic cells prevents prolonged reactions to bacterial lipopolysaccharide in vivo. J Infect Dis. 2009 Dec 1;200(11):1685-93. doi: 10.1086/646616. PMID:19860560 doi:https://dx.doi.org/10.1086/646616
- ↑ Zou B, Jiang W, Han H, Li J, Mao W, Tang Z, Yang Q, Qian G, Qian J, Zeng W, Gu J, Chu T, Zhu N, Zhang W, Yan D, He R, Chu Y, Lu M. Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury. PLoS Pathog. 2017 Jun 16;13(6):e1006436. doi: 10.1371/journal.ppat.1006436., eCollection 2017 Jun. PMID:28622363 doi:https://dx.doi.org/10.1371/journal.ppat.1006436
- ↑ Gorelik A, Illes K, Nagar B. Crystal structure of the mammalian lipopolysaccharide detoxifier. Proc Natl Acad Sci U S A. 2018 Jan 17. pii: 1719834115. doi:, 10.1073/pnas.1719834115. PMID:29343645 doi:https://dx.doi.org/10.1073/pnas.1719834115
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