| 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]
Publication Abstract from PubMed
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.
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[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ 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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