|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of PTPN3 (PTPH1) in complex with a dually phosphorylated MAPK12 peptide== | | ==Crystal structure of PTPN3 (PTPH1) in complex with a dually phosphorylated MAPK12 peptide== |
| - | <StructureSection load='4qum' size='340' side='right' caption='[[4qum]], [[Resolution|resolution]] 2.52Å' scene=''> | + | <StructureSection load='4qum' size='340' side='right'caption='[[4qum]], [[Resolution|resolution]] 2.52Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qum]] is a 2 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=4QUM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QUM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qum]] 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=4QUM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QUM FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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]] 2.516Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qun|4qun]], [[2b49|2b49]], [[1cm8|1cm8]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTPH1, PTPN3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4qum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qum OCA], [https://pdbe.org/4qum PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qum RCSB], [https://www.ebi.ac.uk/pdbsum/4qum PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qum ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qum OCA], [http://pdbe.org/4qum PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qum RCSB], [http://www.ebi.ac.uk/pdbsum/4qum PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qum ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/MK12_HUMAN MK12_HUMAN]] Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PTN3_HUMAN PTN3_HUMAN]] May act at junctions between the membrane and the cytoskeleton. Possesses tyrosine phosphatase activity. [[http://www.uniprot.org/uniprot/MK12_HUMAN MK12_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.<ref>PMID:8633070</ref> <ref>PMID:9430721</ref> <ref>PMID:10848581</ref> <ref>PMID:14592936</ref> <ref>PMID:17724032</ref> <ref>PMID:20605917</ref> <ref>PMID:21172807</ref> | + | [https://www.uniprot.org/uniprot/PTN3_HUMAN PTN3_HUMAN] May act at junctions between the membrane and the cytoskeleton. Possesses tyrosine phosphatase activity. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 25: |
Line 21: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Tyrosine phosphatase|Tyrosine phosphatase]] | + | *[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Protein-tyrosine-phosphatase]] | + | [[Category: Large Structures]] |
| - | [[Category: Chen, K E]] | + | [[Category: Chen KE]] |
| - | [[Category: Meng, T C]] | + | [[Category: Meng TC]] |
| - | [[Category: Wang, A H.J]] | + | [[Category: Wang AHJ]] |
| - | [[Category: Alpha beta]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Function
PTN3_HUMAN May act at junctions between the membrane and the cytoskeleton. Possesses tyrosine phosphatase activity.
Publication Abstract from PubMed
The mitogen-activated protein kinase p38gamma (also known as MAPK12) and its specific phosphatase PTPN3 (also known as PTPH1) cooperate to promote Ras-induced oncogenesis. We determined the architecture of the PTPN3-p38gamma complex by a hybrid method combining x-ray crystallography, small-angle x-ray scattering, and chemical cross-linking coupled to mass spectrometry. A unique feature of the glutamic acid-containing loop (E-loop) of the phosphatase domain defined the substrate specificity of PTPN3 toward fully activated p38gamma. The solution structure revealed the formation of an active-state complex between p38gamma and the phosphatase domain of PTPN3. The PDZ domain of PTPN3 stabilized the active-state complex through an interaction with the PDZ-binding motif of p38gamma. This interaction alleviated autoinhibition of PTPN3, enabling efficient tyrosine dephosphorylation of p38gamma. Our findings may enable structure-based drug design targeting the PTPN3-p38gamma interaction as an anticancer therapeutic.
Reciprocal allosteric regulation of p38gamma and PTPN3 involves a PDZ domain-modulated complex formation.,Chen KE, Lin SY, Wu MJ, Ho MR, Santhanam A, Chou CC, Meng TC, Wang AH Sci Signal. 2014 Oct 14;7(347):ra98. doi: 10.1126/scisignal.2005722. PMID:25314968[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chen KE, Lin SY, Wu MJ, Ho MR, Santhanam A, Chou CC, Meng TC, Wang AH. Reciprocal allosteric regulation of p38gamma and PTPN3 involves a PDZ domain-modulated complex formation. Sci Signal. 2014 Oct 14;7(347):ra98. doi: 10.1126/scisignal.2005722. PMID:25314968 doi:http://dx.doi.org/10.1126/scisignal.2005722
|
