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| | <StructureSection load='6zej' size='340' side='right'caption='[[6zej]], [[Resolution|resolution]] 1.78Å' scene=''> | | <StructureSection load='6zej' size='340' side='right'caption='[[6zej]], [[Resolution|resolution]] 1.78Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6zej]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZEJ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZEJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6zej]] is a 6 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=6ZEJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZEJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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]] 1.78Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PHACTR1, hCG_1818446 ([http://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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphoprotein_phosphatase Phosphoprotein phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.16 3.1.3.16] </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=6zej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zej OCA], [https://pdbe.org/6zej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zej RCSB], [https://www.ebi.ac.uk/pdbsum/6zej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zej ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zej OCA], [http://pdbe.org/6zej PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zej RCSB], [http://www.ebi.ac.uk/pdbsum/6zej PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zej ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/PHAR1_HUMAN PHAR1_HUMAN] Infantile spasms syndrome. The disease is caused by variants affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PP1A_HUMAN PP1A_HUMAN]] Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development.<ref>PMID:17283141</ref> | + | [https://www.uniprot.org/uniprot/PHAR1_HUMAN PHAR1_HUMAN] Binds actin monomers (G actin) and plays a role in multiple processes including the regulation of actin cytoskeleton dynamics, actin stress fibers formation, cell motility and survival, formation of tubules by endothelial cells, and regulation of PPP1CA activity (PubMed:21798305, PubMed:21939755). Involved in the regulation of cortical neuron migration and dendrite arborization (By similarity).[UniProtKB:Q2M3X8]<ref>PMID:21798305</ref> <ref>PMID:21939755</ref> [https://www.uniprot.org/uniprot/PP1A_HUMAN PP1A_HUMAN] Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development.<ref>PMID:17283141</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: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Phosphoprotein phosphatase]]
| + | [[Category: Butler AM]] |
| - | [[Category: Butler, A M]] | + | [[Category: Fedoryshchak R]] |
| - | [[Category: Fedoryshchak, R]] | + | [[Category: Lee R]] |
| - | [[Category: Lee, R]] | + | [[Category: Mouilleron S]] |
| - | [[Category: Mouilleron, S]] | + | [[Category: Prechova M]] |
| - | [[Category: Prechova, M]] | + | [[Category: Treisman R]] |
| - | [[Category: Treisman, R]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Phactr]]
| + | |
| - | [[Category: Phosphatase]]
| + | |
| - | [[Category: Pp1]]
| + | |
| - | [[Category: Rpel]]
| + | |
| Structural highlights
Disease
PHAR1_HUMAN Infantile spasms syndrome. The disease is caused by variants affecting the gene represented in this entry.
Function
PHAR1_HUMAN Binds actin monomers (G actin) and plays a role in multiple processes including the regulation of actin cytoskeleton dynamics, actin stress fibers formation, cell motility and survival, formation of tubules by endothelial cells, and regulation of PPP1CA activity (PubMed:21798305, PubMed:21939755). Involved in the regulation of cortical neuron migration and dendrite arborization (By similarity).[UniProtKB:Q2M3X8][1] [2] PP1A_HUMAN Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development.[3]
Publication Abstract from PubMed
PPP-family phosphatases such as PP1 have little intrinsic specificity. Cofactors can target PP1 to substrates or subcellular locations, but it remains unclear how they might confer sequence-specificity on PP1. The cytoskeletal regulator Phactr1 is a neuronally-enriched PP1 cofactor that is controlled by G-actin. Structural analysis showed that Phactr1 binding remodels PP1's hydrophobic groove, creating a new composite surface adjacent to the catalytic site. Using phosphoproteomics, we identified mouse fibroblast and neuronal Phactr1/PP1 substrates, which include cytoskeletal components and regulators. We determined high-resolution structures of Phactr1/PP1 bound to the dephosphorylated forms of its substrates IRSp53 and spectrin aII. Inversion of the phosphate in these holoenzyme-product complexes supports the proposed PPP-family catalytic mechanism. Substrate sequences C-terminal to the dephosphorylation site make intimate contacts with the composite Phactr1/PP1 surface, which are required for efficient dephosphorylation. Sequence specificity explains why Phactr1/PP1 exhibits orders-of-magnitude enhanced reactivity towards its substrates, compared to apo-PP1 or other PP1 holoenzymes.
Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme.,Fedoryshchak RO, Prechova M, Butler A, Lee R, O'Reilly N, Flynn HR, Snijders AP, Eder N, Ultanir S, Mouilleron S, Treisman R Elife. 2020 Sep 25;9. pii: 61509. doi: 10.7554/eLife.61509. PMID:32975518[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jarray R, Allain B, Borriello L, Biard D, Loukaci A, Larghero J, Hadj-Slimane R, Garbay C, Lepelletier Y, Raynaud F. Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis. Biochimie. 2011 Oct;93(10):1668-75. PMID:21798305 doi:10.1016/j.biochi.2011.07.010
- ↑ Allain B, Jarray R, Borriello L, Leforban B, Dufour S, Liu WQ, Pamonsinlapatham P, Bianco S, Larghero J, Hadj-Slimane R, Garbay C, Raynaud F, Lepelletier Y. Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells. Cell Signal. 2012 Jan;24(1):214-23. PMID:21939755 doi:10.1016/j.cellsig.2011.09.003
- ↑ Mi J, Guo C, Brautigan DL, Larner JM. Protein phosphatase-1alpha regulates centrosome splitting through Nek2. Cancer Res. 2007 Feb 1;67(3):1082-9. PMID:17283141 doi:10.1158/0008-5472.CAN-06-3071
- ↑ Fedoryshchak RO, Prechova M, Butler A, Lee R, O'Reilly N, Flynn HR, Snijders AP, Eder N, Ultanir S, Mouilleron S, Treisman R. Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme. Elife. 2020 Sep 25;9. pii: 61509. doi: 10.7554/eLife.61509. PMID:32975518 doi:http://dx.doi.org/10.7554/eLife.61509
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