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| - | [[Image:1eaz.gif|left|200px]]<br /><applet load="1eaz" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1eaz, resolution 1.4Å" /> | |
| - | '''CRYSTAL STRUCTURE OF THE PHOSPHOINOSITOL (3,4)-BISPHOSPHATE BINDING PH DOMAIN OF TAPP1 FROM HUMAN.'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal structure of the phosphoinositol (3,4)-bisphosphate binding PH domain of TAPP1 from human.== |
| - | Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] and its, immediate breakdown product PtdIns(3,4)P(2) function as second messengers, in growth factor- and insulin-induced signalling pathways. One of the ways, that these 3-phosphoinositides are known to regulate downstream signalling, events is by attracting proteins that possess specific PtdIns-binding, pleckstrin homology (PH) domains to the plasma membrane. Many of these, proteins, such as protein kinase B, phosphoinositide-dependent kinase 1, and the dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1), interact with both PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2) with similar, affinity. Recently, a new PH-domain-containing protein, termed tandem, PH-domain-containing protein (TAPP) 1, was described which is the first, protein reported to bind PtdIns(3,4)P(2) specifically. Here we describe, the crystal structure of the PtdIns(3,4)P(2)-binding PH domain of TAPP1 at, 1.4 A (1 A=0.1 nm) resolution in complex with an ordered citrate molecule., The structure is similar to the known structure of the PH domain of DAPP1, around the D-3 and D-4 inositol-phosphate-binding sites. However, a, glycine residue adjacent to the D-5 inositol-phosphate-binding site in, DAPP1 is substituted for a larger alanine residue in TAPP1, which also, induces a conformational change in the neighbouring residues. We show that, mutation of this glycine to alanine in DAPP1 converts DAPP1 into a, TAPP1-like PH domain that only interacts with PtdIns(3,4)P(2), whereas the, alanine to glycine mutation in TAPP1 permits the TAPP1 PH domain to, interact with PtdIns(3,4,5)P(3). | + | <StructureSection load='1eaz' size='340' side='right'caption='[[1eaz]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1eaz]] is a 1 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=1EAZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EAZ FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></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=1eaz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1eaz OCA], [https://pdbe.org/1eaz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1eaz RCSB], [https://www.ebi.ac.uk/pdbsum/1eaz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1eaz ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PKHA1_HUMAN PKHA1_HUMAN] Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides. May recruit other proteins to the plasma membrane.<ref>PMID:11001876</ref> <ref>PMID:11513726</ref> <ref>PMID:14516276</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/ea/1eaz_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=1eaz ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] and its immediate breakdown product PtdIns(3,4)P(2) function as second messengers in growth factor- and insulin-induced signalling pathways. One of the ways that these 3-phosphoinositides are known to regulate downstream signalling events is by attracting proteins that possess specific PtdIns-binding pleckstrin homology (PH) domains to the plasma membrane. Many of these proteins, such as protein kinase B, phosphoinositide-dependent kinase 1 and the dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1) interact with both PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2) with similar affinity. Recently, a new PH-domain-containing protein, termed tandem PH-domain-containing protein (TAPP) 1, was described which is the first protein reported to bind PtdIns(3,4)P(2) specifically. Here we describe the crystal structure of the PtdIns(3,4)P(2)-binding PH domain of TAPP1 at 1.4 A (1 A=0.1 nm) resolution in complex with an ordered citrate molecule. The structure is similar to the known structure of the PH domain of DAPP1 around the D-3 and D-4 inositol-phosphate-binding sites. However, a glycine residue adjacent to the D-5 inositol-phosphate-binding site in DAPP1 is substituted for a larger alanine residue in TAPP1, which also induces a conformational change in the neighbouring residues. We show that mutation of this glycine to alanine in DAPP1 converts DAPP1 into a TAPP1-like PH domain that only interacts with PtdIns(3,4)P(2), whereas the alanine to glycine mutation in TAPP1 permits the TAPP1 PH domain to interact with PtdIns(3,4,5)P(3). |
| | | | |
| - | ==Disease==
| + | Crystal structure of the phosphatidylinositol 3,4-bisphosphate-binding pleckstrin homology (PH) domain of tandem PH-domain-containing protein 1 (TAPP1): molecular basis of lipid specificity.,Thomas CC, Dowler S, Deak M, Alessi DR, van Aalten DM Biochem J. 2001 Sep 1;358(Pt 2):287-94. PMID:11513726<ref>PMID:11513726</ref> |
| - | Known diseases associated with this structure: Age-related maculopathy, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607772 607772]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1EAZ 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 CIT as [http://en.wikipedia.org/wiki/ligand ligand]. Known structural/functional Site: <scene name='pdbsite=LBS:Lbs Stands For Lipid Binding Site. Cb Atom Responsible F ...'>LBS</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EAZ OCA].
| + | </div> |
| - | | + | <div class="pdbe-citations 1eaz" style="background-color:#fffaf0;"></div> |
| - | ==Reference== | + | == References == |
| - | Crystal structure of the phosphatidylinositol 3,4-bisphosphate-binding pleckstrin homology (PH) domain of tandem PH-domain-containing protein 1 (TAPP1): molecular basis of lipid specificity., Thomas CC, Dowler S, Deak M, Alessi DR, van Aalten DM, Biochem J. 2001 Sep 1;358(Pt 2):287-94. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11513726 11513726]
| + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Aalten, D.M.F.Van.]]
| + | [[Category: Alessi DR]] |
| - | [[Category: Alessi, D.R.]] | + | [[Category: Deak M]] |
| - | [[Category: Deak, M.]] | + | [[Category: Dowler S]] |
| - | [[Category: Dowler, S.]] | + | [[Category: Thomas CC]] |
| - | [[Category: Thomas, C.C.]] | + | [[Category: Van Aalten DMF]] |
| - | [[Category: CIT]] | + | |
| - | [[Category: 4)-bisphosphate]]
| + | |
| - | [[Category: ph domain]]
| + | |
| - | [[Category: phosphatidylinositol (3]]
| + | |
| - | [[Category: signalling]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 15:08:34 2007''
| + | |
| Structural highlights
Function
PKHA1_HUMAN Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides. May recruit other proteins to the plasma membrane.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] and its immediate breakdown product PtdIns(3,4)P(2) function as second messengers in growth factor- and insulin-induced signalling pathways. One of the ways that these 3-phosphoinositides are known to regulate downstream signalling events is by attracting proteins that possess specific PtdIns-binding pleckstrin homology (PH) domains to the plasma membrane. Many of these proteins, such as protein kinase B, phosphoinositide-dependent kinase 1 and the dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1) interact with both PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2) with similar affinity. Recently, a new PH-domain-containing protein, termed tandem PH-domain-containing protein (TAPP) 1, was described which is the first protein reported to bind PtdIns(3,4)P(2) specifically. Here we describe the crystal structure of the PtdIns(3,4)P(2)-binding PH domain of TAPP1 at 1.4 A (1 A=0.1 nm) resolution in complex with an ordered citrate molecule. The structure is similar to the known structure of the PH domain of DAPP1 around the D-3 and D-4 inositol-phosphate-binding sites. However, a glycine residue adjacent to the D-5 inositol-phosphate-binding site in DAPP1 is substituted for a larger alanine residue in TAPP1, which also induces a conformational change in the neighbouring residues. We show that mutation of this glycine to alanine in DAPP1 converts DAPP1 into a TAPP1-like PH domain that only interacts with PtdIns(3,4)P(2), whereas the alanine to glycine mutation in TAPP1 permits the TAPP1 PH domain to interact with PtdIns(3,4,5)P(3).
Crystal structure of the phosphatidylinositol 3,4-bisphosphate-binding pleckstrin homology (PH) domain of tandem PH-domain-containing protein 1 (TAPP1): molecular basis of lipid specificity.,Thomas CC, Dowler S, Deak M, Alessi DR, van Aalten DM Biochem J. 2001 Sep 1;358(Pt 2):287-94. PMID:11513726[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dowler S, Currie RA, Campbell DG, Deak M, Kular G, Downes CP, Alessi DR. Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochem J. 2000 Oct 1;351(Pt 1):19-31. PMID:11001876
- ↑ Thomas CC, Dowler S, Deak M, Alessi DR, van Aalten DM. Crystal structure of the phosphatidylinositol 3,4-bisphosphate-binding pleckstrin homology (PH) domain of tandem PH-domain-containing protein 1 (TAPP1): molecular basis of lipid specificity. Biochem J. 2001 Sep 1;358(Pt 2):287-94. PMID:11513726
- ↑ Kimber WA, Deak M, Prescott AR, Alessi DR. Interaction of the protein tyrosine phosphatase PTPL1 with the PtdIns(3,4)P2-binding adaptor protein TAPP1. Biochem J. 2003 Dec 1;376(Pt 2):525-35. PMID:14516276 doi:10.1042/BJ20031154
- ↑ Thomas CC, Dowler S, Deak M, Alessi DR, van Aalten DM. Crystal structure of the phosphatidylinositol 3,4-bisphosphate-binding pleckstrin homology (PH) domain of tandem PH-domain-containing protein 1 (TAPP1): molecular basis of lipid specificity. Biochem J. 2001 Sep 1;358(Pt 2):287-94. PMID:11513726
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