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| | <StructureSection load='6tp5' size='340' side='right'caption='[[6tp5]], [[Resolution|resolution]] 2.25Å' scene=''> | | <StructureSection load='6tp5' size='340' side='right'caption='[[6tp5]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6tp5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TP5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TP5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6tp5]] 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=6TP5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TP5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</scene>, <scene name='pdbligand=TBU:TERTIARY-BUTYL+ALCOHOL'>TBU</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 2.25Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">P4HTM, PH4 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</scene>, <scene name='pdbligand=TBU:TERTIARY-BUTYL+ALCOHOL'>TBU</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Hypoxia-inducible_factor-proline_dioxygenase Hypoxia-inducible factor-proline dioxygenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.29 1.14.11.29] </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=6tp5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tp5 OCA], [https://pdbe.org/6tp5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tp5 RCSB], [https://www.ebi.ac.uk/pdbsum/6tp5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tp5 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=6tp5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tp5 OCA], [https://pdbe.org/6tp5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tp5 RCSB], [https://www.ebi.ac.uk/pdbsum/6tp5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tp5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/P4HTM_HUMAN P4HTM_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry.
| + | [https://www.uniprot.org/uniprot/P4HTM_HUMAN P4HTM_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/P4HTM_HUMAN P4HTM_HUMAN]] Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.<ref>PMID:17726031</ref>
| + | [https://www.uniprot.org/uniprot/P4HTM_HUMAN P4HTM_HUMAN] Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.<ref>PMID:17726031</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hypoxia-inducible factor-proline dioxygenase]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kallio, J P]] | + | [[Category: Kallio JP]] |
| - | [[Category: Koivunen, P]] | + | [[Category: Koivunen P]] |
| - | [[Category: Koski, M K]] | + | [[Category: Koski MK]] |
| - | [[Category: Myllyharju, J]] | + | [[Category: Myllyharju J]] |
| - | [[Category: Myllykoski, M]] | + | [[Category: Myllykoski M]] |
| - | [[Category: Raasakka, A]] | + | [[Category: Raasakka A]] |
| - | [[Category: Sutinen, A]] | + | [[Category: Sutinen A]] |
| - | [[Category: Wierenga, R K]] | + | [[Category: Wierenga RK]] |
| - | [[Category: 2-oxoglutarate-binding protein]]
| + | |
| - | [[Category: Calcium-binding protein]]
| + | |
| - | [[Category: Double-stranded beta helix]]
| + | |
| - | [[Category: Ef-hand]]
| + | |
| - | [[Category: Hidea syndrome]]
| + | |
| - | [[Category: Iron-binding protein]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Prolyl-4-hydroxylase]]
| + | |
| - | [[Category: Transmembrane protein]]
| + | |
| Structural highlights
6tp5 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 2.25Å |
| Ligands: | , , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
P4HTM_HUMAN The disease is caused by mutations affecting the gene represented in this entry.
Function
P4HTM_HUMAN Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.[1]
Publication Abstract from PubMed
Prolyl 4-hydroxylases (P4Hs) catalyze post-translational hydroxylation of peptidyl proline residues. In addition to collagen P4Hs and hypoxia-inducible factor P4Hs, a third P4H; the poorly characterized endoplasmic reticulum (ER)-localized transmembrane prolyl 4-hydroxylase (P4H-TM); is found in animals. P4H-TM variants are associated with the familiar neurological HIDEA syndrome, but how these variants might contribute to disease is unknown. Here, we explored this question in a structural and functional analysis of soluble human P4H-TM. The crystal structure revealed an EF-domain with two Ca2+-binding motifs inserted within the catalytic domain. A substrate-binding groove was formed between the EF-domain and the conserved core of the catalytic domain. The proximity of the EF-domain to the active site suggests that Ca2+-binding is relevant to the catalytic activity. Functional analysis demonstrated that Ca2+-binding affinity of P4H-TM is within the range of physiological Ca2+ concentration in the ER. P4H-TM was found both as a monomer and a dimer in solution, but the monomer-dimer equilibrium was not regulated by Ca2+. The catalytic site contained bound Fe2+ and N-oxalylglycine, which is an analogue of the cosubstrate 2-oxoglutarate. Comparison to homologous P4H structures complexed with peptide substrates showed that the substrate interacting residues and the lid structure that folds over the substrate are conserved in P4H-TM, whereas the extensive loop structures that surround the substrate-binding groove, generating a negative surface potential, are different. Analysis of the structure suggests that the HIDEA variants cause loss of P4H-TM function. In conclusion, P4H-TM shares key structural elements with other P4Hs while having an unique EF-domain.
Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains.,Myllykoski M, Sutinen A, Koski MK, Kallio JP, Raasakka A, Myllyharju J, Wierenga RK, Koivunen P J Biol Chem. 2020 Dec 17. pii: RA120.016542. doi: 10.1074/jbc.RA120.016542. PMID:33334883[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Koivunen P, Tiainen P, Hyvarinen J, Williams KE, Sormunen R, Klaus SJ, Kivirikko KI, Myllyharju J. An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem. 2007 Oct 19;282(42):30544-52. doi: 10.1074/jbc.M704988200. Epub 2007, Aug 27. PMID:17726031 doi:http://dx.doi.org/10.1074/jbc.M704988200
- ↑ Myllykoski M, Sutinen A, Koski MK, Kallio JP, Raasakka A, Myllyharju J, Wierenga RK, Koivunen P. Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains. J Biol Chem. 2020 Dec 17. pii: RA120.016542. doi: 10.1074/jbc.RA120.016542. PMID:33334883 doi:http://dx.doi.org/10.1074/jbc.RA120.016542
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