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| | ==Human acyl-CoA thioesterases 4 in complex with undecan-2-one-CoA inhibitor== | | ==Human acyl-CoA thioesterases 4 in complex with undecan-2-one-CoA inhibitor== |
| - | <StructureSection load='4gah' size='340' side='right' caption='[[4gah]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='4gah' size='340' side='right'caption='[[4gah]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4gah]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GAH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GAH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4gah]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GAH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GAH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0ET:[[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-4-OXIDANYL-3-PHOSPHONOOXY-OXOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+[(3R)-2,2-DIMETHYL-3-OXIDANYL-4-OXIDANYLIDENE-4-[[3-OXIDANYLIDENE-3-[2-[(2R)-2-OXIDANYLUNDECYL]SULFANYLETHYLAMINO]PROPYL]AMINO]BUTYL]+HYDROGEN+PHOSPHATE'>0ET</scene></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]] 2.3Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTMP, THEM4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0ET:[[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-4-OXIDANYL-3-PHOSPHONOOXY-OXOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+[(3R)-2,2-DIMETHYL-3-OXIDANYL-4-OXIDANYLIDENE-4-[[3-OXIDANYLIDENE-3-[2-[(2R)-2-OXIDANYLUNDECYL]SULFANYLETHYLAMINO]PROPYL]AMINO]BUTYL]+HYDROGEN+PHOSPHATE'>0ET</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acyl-CoA_hydrolase Acyl-CoA hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.2.20 3.1.2.20] </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=4gah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gah OCA], [https://pdbe.org/4gah PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gah RCSB], [https://www.ebi.ac.uk/pdbsum/4gah PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gah ProSAT]</span></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=4gah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gah OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gah RCSB], [http://www.ebi.ac.uk/pdbsum/4gah PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/THEM4_HUMAN THEM4_HUMAN]] Has acyl-CoA thioesterase activity towards medium and long-chain (C14 to C18) fatty acyl-CoA substrates, and probably plays an role in mitochondrial fatty acid metabolism. Plays a role in the apoptotic process, possibly via its regulation of AKT1 activity. According to PubMed:11598301, inhibits AKT1 phosphorylation and activity. According to PubMed:17615157, enhances AKT1 activity by favoring its phosphorylation and translocation to plasma membrane.<ref>PMID:11598301</ref> <ref>PMID:17615157</ref> <ref>PMID:19453107</ref> <ref>PMID:19168129</ref> <ref>PMID:19421406</ref> <ref>PMID:22871024</ref> | + | [https://www.uniprot.org/uniprot/THEM4_HUMAN THEM4_HUMAN] Has acyl-CoA thioesterase activity towards medium and long-chain (C14 to C18) fatty acyl-CoA substrates, and probably plays an role in mitochondrial fatty acid metabolism. Plays a role in the apoptotic process, possibly via its regulation of AKT1 activity. According to PubMed:11598301, inhibits AKT1 phosphorylation and activity. According to PubMed:17615157, enhances AKT1 activity by favoring its phosphorylation and translocation to plasma membrane.<ref>PMID:11598301</ref> <ref>PMID:17615157</ref> <ref>PMID:19453107</ref> <ref>PMID:19168129</ref> <ref>PMID:19421406</ref> <ref>PMID:22871024</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | Human THEM4 (hTHEM4) is comprised of a catalytically active hotdog-fold acyl-CoA thioesterase domain and an N-terminal domain of unknown fold and function. hTHEM4 has been linked to Akt1 regulation and cell apoptosis. Herein, we report the X-ray structure of hHTEM4 bound with undecan-2-one-CoA. Structure guided mutagenesis was carried out to confirm the catalytic residues. The N-terminal domain is shown to be partially comprised of irregular and flexible secondary structure, reminiscent of a protein-binding domain. We demonstrate direct hTHEM4-Akt1 binding by immunoprecipitation and by inhibition of Akt1 kinase activity, thus providing independent evidence that hTHEM4 is an Akt1 negative regulator.
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| - | | + | |
| - | Correlation of Structure and Function in the Human Hotdog-fold Enzyme hTHEM4.,Zhao H, Lim K, Choudry A, Latham JA, Pathak MC, Dominguez D, Luo L, Herzberg O, Dunaway-Mariano D Biochemistry. 2012 Aug 21;51(33):6490-2. Epub 2012 Aug 9. PMID:22871024<ref>PMID:22871024</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Acyl-CoA hydrolase]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Herzberg, O]] | + | [[Category: Large Structures]] |
| - | [[Category: Lim, K]] | + | [[Category: Herzberg O]] |
| - | [[Category: Pathak, M C]] | + | [[Category: Lim K]] |
| - | [[Category: Acyl coa hydrolase]] | + | [[Category: Pathak MC]] |
| - | [[Category: Acyl-coa]]
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| - | [[Category: Akt c-terminal modulating protein]]
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| - | [[Category: Hotdog fold]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| Structural highlights
Function
THEM4_HUMAN Has acyl-CoA thioesterase activity towards medium and long-chain (C14 to C18) fatty acyl-CoA substrates, and probably plays an role in mitochondrial fatty acid metabolism. Plays a role in the apoptotic process, possibly via its regulation of AKT1 activity. According to PubMed:11598301, inhibits AKT1 phosphorylation and activity. According to PubMed:17615157, enhances AKT1 activity by favoring its phosphorylation and translocation to plasma membrane.[1] [2] [3] [4] [5] [6]
References
- ↑ Maira SM, Galetic I, Brazil DP, Kaech S, Ingley E, Thelen M, Hemmings BA. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science. 2001 Oct 12;294(5541):374-80. PMID:11598301 doi:http://dx.doi.org/10.1126/science.1062030
- ↑ Ono H, Sakoda H, Fujishiro M, Anai M, Kushiyama A, Fukushima Y, Katagiri H, Ogihara T, Oka Y, Kamata H, Horike N, Uchijima Y, Kurihara H, Asano T. Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1576-85. Epub 2007 Jul 5. PMID:17615157 doi:http://dx.doi.org/10.1152/ajpcell.00570.2006
- ↑ Zhao H, Martin BM, Bisoffi M, Dunaway-Mariano D. The Akt C-terminal modulator protein is an acyl-CoA thioesterase of the Hotdog-Fold family. Biochemistry. 2009 Jun 23;48(24):5507-9. doi: 10.1021/bi900710w. PMID:19453107 doi:http://dx.doi.org/10.1021/bi900710w
- ↑ Parcellier A, Tintignac LA, Zhuravleva E, Cron P, Schenk S, Bozulic L, Hemmings BA. Carboxy-Terminal Modulator Protein (CTMP) is a mitochondrial protein that sensitizes cells to apoptosis. Cell Signal. 2009 Apr;21(4):639-50. doi: 10.1016/j.cellsig.2009.01.016. Epub 2009, Jan 8. PMID:19168129 doi:http://dx.doi.org/10.1016/j.cellsig.2009.01.016
- ↑ Parcellier A, Tintignac LA, Zhuravleva E, Dummler B, Brazil DP, Hynx D, Cron P, Schenk S, Olivieri V, Hemmings BA. The Carboxy-Terminal Modulator Protein (CTMP) regulates mitochondrial dynamics. PLoS One. 2009;4(5):e5471. doi: 10.1371/journal.pone.0005471. Epub 2009 May 7. PMID:19421406 doi:http://dx.doi.org/10.1371/journal.pone.0005471
- ↑ Zhao H, Lim K, Choudry A, Latham JA, Pathak MC, Dominguez D, Luo L, Herzberg O, Dunaway-Mariano D. Correlation of Structure and Function in the Human Hotdog-fold Enzyme hTHEM4. Biochemistry. 2012 Aug 21;51(33):6490-2. Epub 2012 Aug 9. PMID:22871024 doi:10.1021/bi300968n
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