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| - | [[Image:2q7d.jpg|left|200px]]<br /><applet load="2q7d" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2q7d, resolution 1.60Å" /> | |
| - | '''Crystal Structure of Human Inositol 1,3,4-Trisphosphate 5/6-kinase (ITPK1) in complex with AMPPNP and Mn2+'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal Structure of Human Inositol 1,3,4-Trisphosphate 5/6-kinase (ITPK1) in complex with AMPPNP and Mn2+== |
| - | Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a reversible, poly-specific inositol phosphate kinase that has been implicated as a modifier gene in cystic fibrosis. Upon activation of phospholipase C at the plasma membrane, inositol 1,4,5-trisphosphate enters the cytosol and is inter-converted by an array of kinases and phosphatases into other inositol phosphates with diverse and critical cellular activities. In mammals it has been established that inositol 1,3,4-trisphosphate, produced from inositol 1,4,5-trisphosphate, lies in a branch of the metabolic pathway that is separate from inositol 3,4,5,6-tetrakisphosphate, which inhibits plasma membrane chloride channels. We have determined the molecular mechanism for communication between these two pathways, showing that phosphate is transferred between inositol phosphates via ITPK1-bound nucleotide. Intersubstrate phosphate transfer explains how competing substrates are able to stimulate each others' catalysis by ITPK1. We further show that these features occur in the human protein, but not in plant or protozoan homologues. The high resolution structure of human ITPK1 identifies novel secondary structural features able to impart substrate selectivity and enhance nucleotide binding, thereby promoting intersubstrate phosphate transfer. Our work describes a novel mode of substrate regulation and provides insight into the enzyme evolution of a signaling mechanism from a metabolic role. | + | <StructureSection load='2q7d' size='340' side='right'caption='[[2q7d]], [[Resolution|resolution]] 1.60Å' scene=''> |
| - | | + | == Structural highlights == |
| - | ==About this Structure== | + | <table><tr><td colspan='2'>[[2q7d]] 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=2Q7D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Q7D FirstGlance]. <br> |
| - | 2Q7D is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MN:'>MN</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=ANP:'>ANP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q7D OCA].
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6Å</td></tr> |
| - | | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | ==Reference== | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2q7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q7d OCA], [https://pdbe.org/2q7d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2q7d RCSB], [https://www.ebi.ac.uk/pdbsum/2q7d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2q7d ProSAT]</span></td></tr> |
| - | Integration of inositol phosphate signaling pathways via human ITPK1., Chamberlain PP, Qian X, Stiles AR, Cho J, Jones DH, Lesley SA, Grabau EA, Shears SB, Spraggon G, J Biol Chem. 2007 Sep 21;282(38):28117-25. Epub 2007 Jul 6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17616525 17616525]
| + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/ITPK1_HUMAN ITPK1_HUMAN] Kinase that can phosphorylate various inositol polyphosphate such as Ins(3,4,5,6)P4 or Ins(1,3,4)P3. Phosphorylates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5. This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca(2+)-activated Cl(-) channels, while Ins(1,3,4,5,6)P5 is not. Also phosphorylates Ins(1,3,4)P3 on O-5 and O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway. Also acts as an inositol polyphosphate phosphatase that dephosphorylate Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 to Ins(1,3,4)P3, and Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4. May also act as an isomerase that interconverts the inositol tetrakisphosphate isomers Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 in the presence of ADP and magnesium. Probably acts as the rate-limiting enzyme of the InsP6 pathway. Modifies TNF-alpha-induced apoptosis by interfering with the activation of TNFRSF1A-associated death domain.<ref>PMID:11533064</ref> <ref>PMID:11909533</ref> <ref>PMID:12925536</ref> <ref>PMID:17616525</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/q7/2q7d_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2q7d ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Chamberlain, P P.]] | + | [[Category: Chamberlain PP]] |
| - | [[Category: Lesley, S A.]] | + | [[Category: Lesley SA]] |
| - | [[Category: Spraggon, G.]] | + | [[Category: Spraggon G]] |
| - | [[Category: ANP]]
| + | |
| - | [[Category: MN]]
| + | |
| - | [[Category: SO4]]
| + | |
| - | [[Category: 3]]
| + | |
| - | [[Category: 4-5/6-kinase]]
| + | |
| - | [[Category: inositol]]
| + | |
| - | [[Category: inositol 1]]
| + | |
| - | [[Category: inositol kinase]]
| + | |
| - | [[Category: inositol phosphate]]
| + | |
| - | [[Category: inositolphosphate]]
| + | |
| - | [[Category: itpk1]]
| + | |
| - | [[Category: kinase]]
| + | |
| - | [[Category: phosphate]]
| + | |
| - | [[Category: polyphosphate]]
| + | |
| - | [[Category: transferase]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:36:49 2008''
| + | |
| Structural highlights
Function
ITPK1_HUMAN Kinase that can phosphorylate various inositol polyphosphate such as Ins(3,4,5,6)P4 or Ins(1,3,4)P3. Phosphorylates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5. This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca(2+)-activated Cl(-) channels, while Ins(1,3,4,5,6)P5 is not. Also phosphorylates Ins(1,3,4)P3 on O-5 and O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway. Also acts as an inositol polyphosphate phosphatase that dephosphorylate Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 to Ins(1,3,4)P3, and Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4. May also act as an isomerase that interconverts the inositol tetrakisphosphate isomers Ins(1,3,4,5)P4 and Ins(1,3,4,6)P4 in the presence of ADP and magnesium. Probably acts as the rate-limiting enzyme of the InsP6 pathway. Modifies TNF-alpha-induced apoptosis by interfering with the activation of TNFRSF1A-associated death domain.[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Wilson MP, Sun Y, Cao L, Majerus PW. Inositol 1,3,4-trisphosphate 5/6-kinase is a protein kinase that phosphorylates the transcription factors c-Jun and ATF-2. J Biol Chem. 2001 Nov 2;276(44):40998-1004. Epub 2001 Aug 31. PMID:11533064 doi:http://dx.doi.org/10.1074/jbc.M106605200
- ↑ Ho MW, Yang X, Carew MA, Zhang T, Hua L, Kwon YU, Chung SK, Adelt S, Vogel G, Riley AM, Potter BV, Shears SB. Regulation of Ins(3,4,5,6)P(4) signaling by a reversible kinase/phosphatase. Curr Biol. 2002 Mar 19;12(6):477-82. PMID:11909533
- ↑ Sun Y, Mochizuki Y, Majerus PW. Inositol 1,3,4-trisphosphate 5/6-kinase inhibits tumor necrosis factor-induced apoptosis. J Biol Chem. 2003 Oct 31;278(44):43645-53. Epub 2003 Aug 18. PMID:12925536 doi:http://dx.doi.org/10.1074/jbc.M300674200
- ↑ Chamberlain PP, Qian X, Stiles AR, Cho J, Jones DH, Lesley SA, Grabau EA, Shears SB, Spraggon G. Integration of inositol phosphate signaling pathways via human ITPK1. J Biol Chem. 2007 Sep 21;282(38):28117-25. Epub 2007 Jul 6. PMID:17616525 doi:10.1074/jbc.M703121200
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