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| | ==Crystal structure of LIMK1 mutant D460N in complex with full-length cofilin-1== | | ==Crystal structure of LIMK1 mutant D460N in complex with full-length cofilin-1== |
| - | <StructureSection load='5hvk' size='340' side='right' caption='[[5hvk]], [[Resolution|resolution]] 3.50Å' scene=''> | + | <StructureSection load='5hvk' size='340' side='right'caption='[[5hvk]], [[Resolution|resolution]] 3.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5hvk]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HVK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HVK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5hvk]] is a 4 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=5HVK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HVK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 3.5Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5hvj|5hvj]]</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=5hvk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvk OCA], [https://pdbe.org/5hvk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hvk RCSB], [https://www.ebi.ac.uk/pdbsum/5hvk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvk 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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5hvk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvk OCA], [http://pdbe.org/5hvk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hvk RCSB], [http://www.ebi.ac.uk/pdbsum/5hvk PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN]] Williams syndrome. Note=LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. | + | [https://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN] Williams syndrome. Note=LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN]] Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes.<ref>PMID:10196227</ref> <ref>PMID:10436159</ref> <ref>PMID:11832213</ref> <ref>PMID:12807904</ref> <ref>PMID:15660133</ref> <ref>PMID:16230460</ref> <ref>PMID:18028908</ref> [[http://www.uniprot.org/uniprot/COF1_HUMAN COF1_HUMAN]] Binds to F-actin and exhibits pH-sensitive F-actin depolymerizing activity. Regulates actin cytoskeleton dynamics. Important for normal progress through mitosis and normal cytokinesis. Plays a role in the regulation of cell morphology and cytoskeletal organization.<ref>PMID:15580268</ref> <ref>PMID:21834987</ref> | + | [https://www.uniprot.org/uniprot/LIMK1_HUMAN LIMK1_HUMAN] Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes.<ref>PMID:10196227</ref> <ref>PMID:10436159</ref> <ref>PMID:11832213</ref> <ref>PMID:12807904</ref> <ref>PMID:15660133</ref> <ref>PMID:16230460</ref> <ref>PMID:18028908</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: Non-specific serine/threonine protein kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Boggon, T J]] | + | [[Category: Large Structures]] |
| - | [[Category: Hamill, S]] | + | [[Category: Boggon TJ]] |
| - | [[Category: Kinase substrate actin-remodeling]] | + | [[Category: Hamill S]] |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
LIMK1_HUMAN Williams syndrome. Note=LIMK1 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.
Function
LIMK1_HUMAN Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Activated by upstream kinases including ROCK1, PAK1 and PAK4, which phosphorylate LIMK1 on a threonine residue located in its activation loop. LIMK1 subsequently phosphorylates and inactivates the actin binding/depolymerizing factors cofilin-1/CFL1, cofilin-2/CFL2 and destrin/DSTN, thereby preventing the cleavage of filamentous actin (F-actin), and stabilizing the actin cytoskeleton. In this way LIMK1 regulates several actin-dependent biological processes including cell motility, cell cycle progression, and differentiation. Phosphorylates TPPP on serine residues, thereby promoting microtubule disassembly. Stimulates axonal outgrowth and may be involved in brain development. Isoform 3 has a dominant negative effect on actin cytoskeletal changes.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Cofilin/actin-depolymerizing factor (ADF) proteins are critical nodes that relay signals from protein kinase cascades to the actin cytoskeleton, in particular through site-specific phosphorylation at residue Ser3. This is important for regulation of the roles of cofilin in severing and stabilizing actin filaments. Consequently, cofilin/ADF Ser3 phosphorylation is tightly controlled as an almost exclusive substrate for LIM kinases. Here we determine the LIMK1:cofilin-1 co-crystal structure. We find an interface that is distinct from canonical kinase-substrate interactions. We validate this previously unobserved mechanism for high-fidelity kinase-substrate recognition by in vitro kinase assays, examination of cofilin phosphorylation in mammalian cells, and functional analysis in S. cerevisiae. The interface is conserved across all LIM kinases. Remarkably, we also observe both pre- and postphosphotransfer states in the same crystal lattice. This study therefore provides a molecular understanding of how kinase-substrate recognition acts as a gatekeeper to regulate actin cytoskeletal dynamics.
Structural Basis for Noncanonical Substrate Recognition of Cofilin/ADF Proteins by LIM Kinases.,Hamill S, Lou HJ, Turk BE, Boggon TJ Mol Cell. 2016 May 5;62(3):397-408. doi: 10.1016/j.molcel.2016.04.001. PMID:27153537[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Edwards DC, Gill GN. Structural features of LIM kinase that control effects on the actin cytoskeleton. J Biol Chem. 1999 Apr 16;274(16):11352-61. PMID:10196227
- ↑ Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999 Aug 6;285(5429):895-8. PMID:10436159
- ↑ Niwa R, Nagata-Ohashi K, Takeichi M, Mizuno K, Uemura T. Control of actin reorganization by Slingshot, a family of phosphatases that dephosphorylate ADF/cofilin. Cell. 2002 Jan 25;108(2):233-46. PMID:11832213
- ↑ Kaji N, Ohashi K, Shuin M, Niwa R, Uemura T, Mizuno K. Cell cycle-associated changes in Slingshot phosphatase activity and roles in cytokinesis in animal cells. J Biol Chem. 2003 Aug 29;278(35):33450-5. Epub 2003 Jun 14. PMID:12807904 doi:10.1074/jbc.M305802200
- ↑ Soosairajah J, Maiti S, Wiggan O, Sarmiere P, Moussi N, Sarcevic B, Sampath R, Bamburg JR, Bernard O. Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J. 2005 Feb 9;24(3):473-86. Epub 2005 Jan 20. PMID:15660133 doi:7600543
- ↑ Nishita M, Tomizawa C, Yamamoto M, Horita Y, Ohashi K, Mizuno K. Spatial and temporal regulation of cofilin activity by LIM kinase and Slingshot is critical for directional cell migration. J Cell Biol. 2005 Oct 24;171(2):349-59. Epub 2005 Oct 17. PMID:16230460 doi:10.1083/jcb.200504029
- ↑ Acevedo K, Li R, Soo P, Suryadinata R, Sarcevic B, Valova VA, Graham ME, Robinson PJ, Bernard O. The phosphorylation of p25/TPPP by LIM kinase 1 inhibits its ability to assemble microtubules. Exp Cell Res. 2007 Dec 10;313(20):4091-106. PMID:18028908 doi:10.1016/j.yexcr.2007.08.012
- ↑ Hamill S, Lou HJ, Turk BE, Boggon TJ. Structural Basis for Noncanonical Substrate Recognition of Cofilin/ADF Proteins by LIM Kinases. Mol Cell. 2016 May 5;62(3):397-408. doi: 10.1016/j.molcel.2016.04.001. PMID:27153537 doi:http://dx.doi.org/10.1016/j.molcel.2016.04.001
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