6wly
From Proteopedia
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==PAK4 kinase domain in complex with LIMK1 Thr508 substrate peptide== | ==PAK4 kinase domain in complex with LIMK1 Thr508 substrate peptide== | ||
| - | <StructureSection load='6wly' size='340' side='right'caption='[[6wly]]' scene=''> | + | <StructureSection load='6wly' size='340' side='right'caption='[[6wly]], [[Resolution|resolution]] 1.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WLY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WLY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6wly]] 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=6WLY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WLY FirstGlance]. <br> |
| - | </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=6wly FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wly OCA], [http://pdbe.org/6wly PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wly RCSB], [http://www.ebi.ac.uk/pdbsum/6wly PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wly ProSAT]</span></td></tr> | + | </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></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PAK4, KIAA1142 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://proteopedia.org/fgij/fg.htm?mol=6wly FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wly OCA], [http://pdbe.org/6wly PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wly RCSB], [http://www.ebi.ac.uk/pdbsum/6wly PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wly ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == 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. | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PAK4_HUMAN PAK4_HUMAN]] Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN.<ref>PMID:11278822</ref> <ref>PMID:11313478</ref> <ref>PMID:14560027</ref> <ref>PMID:15660133</ref> <ref>PMID:20507994</ref> <ref>PMID:20805321</ref> <ref>PMID:20631255</ref> [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Many serine/threonine protein kinases discriminate between serine and threonine substrates as a filter to control signaling output. Among these, the p21-activated kinase (PAK) group strongly favors phosphorylation of Ser over Thr residues. PAK4, a group II PAK, almost exclusively phosphorylates its substrates on serine residues. The only well documented exception is LIM domain kinase 1 (LIMK1), which is phosphorylated on an activation loop threonine (Thr508) to promote its catalytic activity. To understand the molecular and kinetic basis for PAK4 substrate selectivity we compared its mode of recognition of LIMK1 (Thr508) with that of a known serine substrate, beta-catenin (Ser675). We determined X-ray crystal structures of PAK4 in complex with synthetic peptides corresponding to its phosphorylation sites in LIMK1 and beta-catenin to 1.9 A and 2.2 A resolution, respectively. We found that the PAK4 DFG+1 residue, a key determinant of phosphoacceptor preference, adopts a sub-optimal orientation when bound to LIMK1 compared to beta-catenin. In peptide kinase activity assays, we find that phosphoacceptor identity impacts catalytic efficiency but does not affect the Km value for both phosphorylation sites. Although catalytic efficiency of wild-type LIMK1 and beta-catenin are equivalent, T508S mutation of LIMK1 creates a highly efficient substrate. These results suggest suboptimal phosphorylation of LIMK1 as a mechanism for controlling the dynamics of substrate phosphorylation by PAK4. | ||
| + | |||
| + | Recognition of physiological phosphorylation sites by p21-activated kinase 4.,Chetty AK, Sexton JA, Hak Ha B, Turk BE, Boggon TJ J Struct Biol. 2020 Jun 22:107553. doi: 10.1016/j.jsb.2020.107553. PMID:32585314<ref>PMID:32585314</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6wly" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Boggon | + | [[Category: Non-specific serine/threonine protein kinase]] |
| - | [[Category: Chetty | + | [[Category: Boggon, T J]] |
| - | [[Category: Ha | + | [[Category: Chetty, A K]] |
| + | [[Category: Ha, B H]] | ||
| + | [[Category: Lim kinase 1]] | ||
| + | [[Category: Limk1]] | ||
| + | [[Category: Phosphopeptide]] | ||
| + | [[Category: Serine/threonine kinase pak4]] | ||
| + | [[Category: Thr508]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 14:41, 8 July 2020
PAK4 kinase domain in complex with LIMK1 Thr508 substrate peptide
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