4wn5

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Crystal structure of the C-terminal Per-Arnt-Sim (PASb) of human HIF-3alpha9 bound to 18:1-1-monoacylglycerolCrystal structure of the C-terminal Per-Arnt-Sim (PASb) of human HIF-3alpha9 bound to 18:1-1-monoacylglycerol

Structural highlights

4wn5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.15Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HIF3A_HUMAN Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:11573933, PubMed:16126907, PubMed:19694616, PubMed:20416395, PubMed:21069422). Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis (By similarity).[UniProtKB:Q0VBL6][1] [2] [3] [4] [5] Isoform 2: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Also inhibits hypoxia-inducible ARNT-mediated gene expression.[6] Isoform 3: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.[7] [8] [9] isoform 4: Attenuates the ability of transcription factor HIF1A and EPAS1/HIF2A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation (PubMed:16126907, PubMed:17998805, PubMed:19694616, PubMed:20416395). May act as a tumor suppressor and inhibits malignant cell transformation (PubMed:17998805).[10] [11] [12] [13] Isoform 5: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.[14]

Publication Abstract from PubMed

Hypoxia-inducible transcription factors (HIF) form heterodimeric complexes that mediate cell responses to hypoxia. The oxygen-dependent stability and activity of the HIF-alpha subunits is traditionally associated to post-translational modifications such as hydroxylation, acetylation, ubiquitination, and phosphorylation. Here we report novel evidence showing that unsaturated fatty acids are naturally occurring, non-covalent structural ligands of HIF-3alpha, thus providing the initial framework for exploring its exceptional role as a lipid sensor under hypoxia.

Unsaturated fatty acids as high-affinity ligands of the C-terminal Per-ARNT-Sim domain from the Hypoxia-inducible factor 3alpha.,Fala AM, Oliveira JF, Adamoski D, Aricetti JA, Dias MM, Dias MVB, Sforca ML, Lopes-de-Oliveira PS, Rocco SA, Caldana C, Dias SMG, Ambrosio ALB Sci Rep. 2015 Aug 3;5:12698. doi: 10.1038/srep12698. PMID:26237540[15]

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

See Also

References

  1. ↑ Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N. Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun. 2001 Oct 5;287(4):808-13. PMID:11573933 doi:http://dx.doi.org/10.1006/bbrc.2001.5659
  2. ↑ Maynard MA, Evans AJ, Hosomi T, Hara S, Jewett MA, Ohh M. Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma. FASEB J. 2005 Sep;19(11):1396-406. PMID:16126907 doi:http://dx.doi.org/10.1096/fj.05-3788com
  3. ↑ Tanaka T, Wiesener M, Bernhardt W, Eckardt KU, Warnecke C. The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction. Biochem J. 2009 Oct 23;424(1):143-51. doi: 10.1042/BJ20090120. PMID:19694616 doi:http://dx.doi.org/10.1042/BJ20090120
  4. ↑ Pasanen A, Heikkila M, Rautavuoma K, Hirsila M, Kivirikko KI, Myllyharju J. Hypoxia-inducible factor (HIF)-3alpha is subject to extensive alternative splicing in human tissues and cancer cells and is regulated by HIF-1 but not HIF-2. Int J Biochem Cell Biol. 2010 Jul;42(7):1189-200. doi:, 10.1016/j.biocel.2010.04.008. Epub 2010 Apr 21. PMID:20416395 doi:http://dx.doi.org/10.1016/j.biocel.2010.04.008
  5. ↑ Augstein A, Poitz DM, Braun-Dullaeus RC, Strasser RH, Schmeisser A. Cell-specific and hypoxia-dependent regulation of human HIF-3alpha: inhibition of the expression of HIF target genes in vascular cells. Cell Mol Life Sci. 2011 Aug;68(15):2627-42. doi: 10.1007/s00018-010-0575-4. Epub , 2010 Nov 11. PMID:21069422 doi:http://dx.doi.org/10.1007/s00018-010-0575-4
  6. ↑ Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N. Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun. 2001 Oct 5;287(4):808-13. PMID:11573933 doi:http://dx.doi.org/10.1006/bbrc.2001.5659
  7. ↑ Tanaka T, Wiesener M, Bernhardt W, Eckardt KU, Warnecke C. The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction. Biochem J. 2009 Oct 23;424(1):143-51. doi: 10.1042/BJ20090120. PMID:19694616 doi:http://dx.doi.org/10.1042/BJ20090120
  8. ↑ Pasanen A, Heikkila M, Rautavuoma K, Hirsila M, Kivirikko KI, Myllyharju J. Hypoxia-inducible factor (HIF)-3alpha is subject to extensive alternative splicing in human tissues and cancer cells and is regulated by HIF-1 but not HIF-2. Int J Biochem Cell Biol. 2010 Jul;42(7):1189-200. doi:, 10.1016/j.biocel.2010.04.008. Epub 2010 Apr 21. PMID:20416395 doi:http://dx.doi.org/10.1016/j.biocel.2010.04.008
  9. ↑ Augstein A, Poitz DM, Braun-Dullaeus RC, Strasser RH, Schmeisser A. Cell-specific and hypoxia-dependent regulation of human HIF-3alpha: inhibition of the expression of HIF target genes in vascular cells. Cell Mol Life Sci. 2011 Aug;68(15):2627-42. doi: 10.1007/s00018-010-0575-4. Epub , 2010 Nov 11. PMID:21069422 doi:http://dx.doi.org/10.1007/s00018-010-0575-4
  10. ↑ Maynard MA, Evans AJ, Hosomi T, Hara S, Jewett MA, Ohh M. Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma. FASEB J. 2005 Sep;19(11):1396-406. PMID:16126907 doi:http://dx.doi.org/10.1096/fj.05-3788com
  11. ↑ Maynard MA, Evans AJ, Shi W, Kim WY, Liu FF, Ohh M. Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle. 2007 Nov 15;6(22):2810-6. Epub 2007 Aug 29. PMID:17998805
  12. ↑ Tanaka T, Wiesener M, Bernhardt W, Eckardt KU, Warnecke C. The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction. Biochem J. 2009 Oct 23;424(1):143-51. doi: 10.1042/BJ20090120. PMID:19694616 doi:http://dx.doi.org/10.1042/BJ20090120
  13. ↑ Pasanen A, Heikkila M, Rautavuoma K, Hirsila M, Kivirikko KI, Myllyharju J. Hypoxia-inducible factor (HIF)-3alpha is subject to extensive alternative splicing in human tissues and cancer cells and is regulated by HIF-1 but not HIF-2. Int J Biochem Cell Biol. 2010 Jul;42(7):1189-200. doi:, 10.1016/j.biocel.2010.04.008. Epub 2010 Apr 21. PMID:20416395 doi:http://dx.doi.org/10.1016/j.biocel.2010.04.008
  14. ↑ Augstein A, Poitz DM, Braun-Dullaeus RC, Strasser RH, Schmeisser A. Cell-specific and hypoxia-dependent regulation of human HIF-3alpha: inhibition of the expression of HIF target genes in vascular cells. Cell Mol Life Sci. 2011 Aug;68(15):2627-42. doi: 10.1007/s00018-010-0575-4. Epub , 2010 Nov 11. PMID:21069422 doi:http://dx.doi.org/10.1007/s00018-010-0575-4
  15. ↑ Fala AM, Oliveira JF, Adamoski D, Aricetti JA, Dias MM, Dias MVB, Sforca ML, Lopes-de-Oliveira PS, Rocco SA, Caldana C, Dias SMG, Ambrosio ALB. Unsaturated fatty acids as high-affinity ligands of the C-terminal Per-ARNT-Sim domain from the Hypoxia-inducible factor 3alpha. Sci Rep. 2015 Aug 3;5:12698. doi: 10.1038/srep12698. PMID:26237540 doi:http://dx.doi.org/10.1038/srep12698

4wn5, resolution 1.15Å

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