6r6t

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of mouse cis-aconitate decarboxylase

Structural highlights

6r6t 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 2.535Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

IRG1_MOUSE Cis-aconitate decarboxylase that catalyzes production of itaconate and is involved in the inhibition of the inflammatory response (PubMed:23609450, PubMed:23610393, PubMed:30635240, PubMed:31548418). Acts as a negative regulator of the Toll-like receptors (TLRs)-mediated inflammatory innate response by stimulating the tumor necrosis factor alpha-induced protein TNFAIP3 expression via reactive oxygen species (ROS) in LPS-tolerized macrophages (PubMed:23609450). Involved in antimicrobial response of innate immune cells; ACOD1-mediated itaconic acid production contributes to the antimicrobial activity of macrophages by generating itaconate, leading to alkylation of proteins, such as TFEB (PubMed:23610393, PubMed:35662396). Involved in antiviral response following infection by flavivirus in neurons: ACOD1-mediated itaconate production inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (PubMed:30635240). Plays a role in the embryo implantation (PubMed:14500577).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

cis-Aconitate decarboxylase (CAD, also known as ACOD1 or Irg1) converts cis-aconitate to itaconate and plays central roles in linking innate immunity with metabolism and in the biotechnological production of itaconic acid by Aspergillus terreus We have elucidated the crystal structures of human and murine CADs and compared their enzymological properties to CAD from A. terreus Recombinant CAD is fully active in vitro without a cofactor. Murine CAD has the highest catalytic activity, whereas Aspergillus CAD is best adapted to a more acidic pH. CAD is not homologous to any known decarboxylase and appears to have evolved from prokaryotic enzymes that bind negatively charged substrates. CADs are homodimers, the active center is located in the interface between 2 distinct subdomains, and structural modeling revealed conservation in zebrafish and Aspergillus We identified 8 active-site residues critical for CAD function and rare naturally occurring human mutations in the active site that abolished CAD activity, as well as a variant (Asn152Ser) that increased CAD activity and is common (allele frequency 20%) in African ethnicity. These results open the way for 1) assessing the potential impact of human CAD variants on disease risk at the population level, 2) developing therapeutic interventions to modify CAD activity, and 3) improving CAD efficiency for biotechnological production of itaconic acid.

Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis.,Chen F, Lukat P, Iqbal AA, Saile K, Kaever V, van den Heuvel J, Blankenfeldt W, Bussow K, Pessler F Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20644-20654. doi:, 10.1073/pnas.1908770116. Epub 2019 Sep 23. PMID:31548418^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cheon YP, Xu X, Bagchi MK, Bagchi IC. Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. Endocrinology. 2003 Dec;144(12):5623-30. PMID:14500577 doi:10.1210/en.2003-0585
↑ Li Y, Zhang P, Wang C, Han C, Meng J, Liu X, Xu S, Li N, Wang Q, Shi X, Cao X. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J Biol Chem. 2013 Jun 7;288(23):16225-34. doi: 10.1074/jbc.M113.454538. Epub 2013, Apr 22. PMID:23609450 doi:http://dx.doi.org/10.1074/jbc.M113.454538
↑ Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T, Wegner A, Tallam A, Rausell A, Buttini M, Linster CL, Medina E, Balling R, Hiller K. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7820-5. doi:, 10.1073/pnas.1218599110. Epub 2013 Apr 22. PMID:23610393 doi:http://dx.doi.org/10.1073/pnas.1218599110
↑ Daniels BP, Kofman SB, Smith JR, Norris GT, Snyder AG, Kolb JP, Gao X, Locasale JW, Martinez J, Gale M Jr, Loo YM, Oberst A. The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons. Immunity. 2019 Jan 15;50(1):64-76.e4. PMID:30635240 doi:10.1016/j.immuni.2018.11.017
↑ Chen F, Lukat P, Iqbal AA, Saile K, Kaever V, van den Heuvel J, Blankenfeldt W, Bussow K, Pessler F. Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20644-20654. doi:, 10.1073/pnas.1908770116. Epub 2019 Sep 23. PMID:31548418 doi:http://dx.doi.org/10.1073/pnas.1908770116
↑ Zhang Z, Chen C, Yang F, Zeng YX, Sun P, Liu P, Li X. Itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Mol Cell. 2022 Aug 4;82(15):2844-2857.e10. PMID:35662396 doi:10.1016/j.molcel.2022.05.009
↑ Chen F, Lukat P, Iqbal AA, Saile K, Kaever V, van den Heuvel J, Blankenfeldt W, Bussow K, Pessler F. Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20644-20654. doi:, 10.1073/pnas.1908770116. Epub 2019 Sep 23. PMID:31548418 doi:http://dx.doi.org/10.1073/pnas.1908770116

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6r6t"

@@ Line 3: / Line 3: @@
 <StructureSection load='6r6t' size='340' side='right'caption='[[6r6t]], [[Resolution|resolution]] 2.54&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6r6t]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R6T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R6T FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6r6t]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R6T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R6T FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Acod1, Irg1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.535&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6r6t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6t OCA], [http://pdbe.org/6r6t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r6t RCSB], [http://www.ebi.ac.uk/pdbsum/6r6t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6t ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6r6t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6t OCA], [https://pdbe.org/6r6t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r6t RCSB], [https://www.ebi.ac.uk/pdbsum/6r6t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6t ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/IRG1_MOUSE IRG1_MOUSE] Cis-aconitate decarboxylase that catalyzes production of itaconate and is involved in the inhibition of the inflammatory response (PubMed:23609450, PubMed:23610393, PubMed:30635240, PubMed:31548418). Acts as a negative regulator of the Toll-like receptors (TLRs)-mediated inflammatory innate response by stimulating the tumor necrosis factor alpha-induced protein TNFAIP3 expression via reactive oxygen species (ROS) in LPS-tolerized macrophages (PubMed:23609450). Involved in antimicrobial response of innate immune cells; ACOD1-mediated itaconic acid production contributes to the antimicrobial activity of macrophages by generating itaconate, leading to alkylation of proteins, such as TFEB (PubMed:23610393, PubMed:35662396). Involved in antiviral response following infection by flavivirus in neurons: ACOD1-mediated itaconate production inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (PubMed:30635240). Plays a role in the embryo implantation (PubMed:14500577).<ref>PMID:14500577</ref> <ref>PMID:23609450</ref> <ref>PMID:23610393</ref> <ref>PMID:30635240</ref> <ref>PMID:31548418</ref> <ref>PMID:35662396</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 23: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Lk3 transgenic mice]]
+[[Category: Mus musculus]]
-[[Category: Blankenfeldt, W]]
+[[Category: Blankenfeldt W]]
-[[Category: Buessow, K]]
+[[Category: Buessow K]]
-[[Category: Chen, F]]
+[[Category: Chen F]]
-[[Category: Lukat, P]]
+[[Category: Lukat P]]
-[[Category: Pessler, F]]
+[[Category: Pessler F]]
-[[Category: Saile, K]]
+[[Category: Saile K]]
-[[Category: Antimicrobial]]
-[[Category: Cis-aconitate]]
-[[Category: Decarboxylase]]
-[[Category: Immunity]]
-[[Category: Inflammatory response]]
-[[Category: Innate immunity]]
-[[Category: Itaconate]]
-[[Category: Lyase]]

6r6t

From Proteopedia

Current revision

Crystal structure of mouse cis-aconitate decarboxylase

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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