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| | <StructureSection load='5qu2' size='340' side='right'caption='[[5qu2]], [[Resolution|resolution]] 1.04Å' scene=''> | | <StructureSection load='5qu2' size='340' side='right'caption='[[5qu2]], [[Resolution|resolution]] 1.04Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5qu2]] is a 4 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=5QU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QU2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5qu2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5QU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5QU2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.04Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NCK1, NCK ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5qu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qu2 OCA], [https://pdbe.org/5qu2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qu2 RCSB], [https://www.ebi.ac.uk/pdbsum/5qu2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qu2 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=5qu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5qu2 OCA], [https://pdbe.org/5qu2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5qu2 RCSB], [https://www.ebi.ac.uk/pdbsum/5qu2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5qu2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/NCK1_HUMAN NCK1_HUMAN]] Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.<ref>PMID:10026169</ref> <ref>PMID:16835242</ref> <ref>PMID:17803907</ref>
| + | [https://www.uniprot.org/uniprot/NCK1_HUMAN NCK1_HUMAN] Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.<ref>PMID:10026169</ref> <ref>PMID:16835242</ref> <ref>PMID:17803907</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: Rudolph, M G]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Adaptor]] | + | [[Category: Rudolph MG]] |
| - | [[Category: Domain swap]]
| + | |
| - | [[Category: Peptide binding]]
| + | |
| - | [[Category: Sh3 domain]]
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| - | [[Category: Signaling protein]]
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| Structural highlights
Function
NCK1_HUMAN Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.[1] [2] [3]
Publication Abstract from PubMed
Activation of the T cell receptor (TCR) results in binding of the adapter protein Nck (noncatalytic region of tyrosine kinase) to the CD3 subunit of the TCR. The interaction was suggested to be important for the amplification of TCR signals and is governed by a proline-rich sequence (PRS) in CD3 that binds to the first Src homology 3 (SH3) domain of Nck (Nck-SH3.1). Inhibition of this protein/protein interaction ameliorated inflammatory symptoms in mouse models of multiple sclerosis, psoriasis, and asthma. A small molecule, AX-024, was reported to inhibit the Nck/CD3 interaction by physically binding to the Nck1-SH3.1 domain, suggesting a route to develop an inhibitor of the Nck1/CD3 interaction for modulating TCR activity in autoimmune and inflammatory diseases. We show here that AX-024 reduces T cell proliferation upon weak TCR stimulation but does not significantly affect phosphorylation of Zap70 (zeta chain of T cell receptor-associated protein kinase 70). We also find that AX-024 is likely not involved in modulating the Nck/TCR interaction but probably has other targets in T cells. An array of biophysical techniques did not detect a direct interaction between AX-024 and Nck-SH3.1 in vitro Crystal structures of the Nck-SH3.1 domain revealed its binding mode to the PRS in CD3. The SH3 domain tends to generate homodimers through a domain swap. Domain swaps observed previously in other SH3 domains indicate a general propensity of this protein fold to exchange structural elements. The swapped form of Nck-SH3.1 is unable to bind CD3, possibly representing an inactive form of Nck in cells.
Small molecule AX-024 reduces T cell proliferation independently of CD3/Nck1 interaction, which is governed by a domain swap in the Nck1-SH3.1 domain.,Richter K, Rufer AC, Muller M, Burger D, Casagrande F, Grossenbacher T, Huber S, Hug MN, Koldewey P, D'Osualdo A, Schlatter D, Stoll T, Rudolph MG J Biol Chem. 2020 Jun 5;295(23):7849-7864. doi: 10.1074/jbc.RA120.012788. Epub, 2020 Apr 21. PMID:32317279[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Braverman LE, Quilliam LA. Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck. J Biol Chem. 1999 Feb 26;274(9):5542-9. PMID:10026169
- ↑ Latreille M, Larose L. Nck in a complex containing the catalytic subunit of protein phosphatase 1 regulates eukaryotic initiation factor 2alpha signaling and cell survival to endoplasmic reticulum stress. J Biol Chem. 2006 Sep 8;281(36):26633-44. Epub 2006 Jul 11. PMID:16835242 doi:http://dx.doi.org/M513556200
- ↑ Kremer BE, Adang LA, Macara IG. Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell. 2007 Sep 7;130(5):837-50. PMID:17803907 doi:http://dx.doi.org/10.1016/j.cell.2007.06.053
- ↑ Richter K, Rufer AC, Muller M, Burger D, Casagrande F, Grossenbacher T, Huber S, Hug MN, Koldewey P, D'Osualdo A, Schlatter D, Stoll T, Rudolph MG. Small molecule AX-024 reduces T cell proliferation independently of CD3/Nck1 interaction, which is governed by a domain swap in the Nck1-SH3.1 domain. J Biol Chem. 2020 Jun 5;295(23):7849-7864. doi: 10.1074/jbc.RA120.012788. Epub, 2020 Apr 21. PMID:32317279 doi:http://dx.doi.org/10.1074/jbc.RA120.012788
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