3s8e: Difference between revisions
New page: '''Unreleased structure''' The entry 3s8e is ON HOLD Authors: Velazquez-Delgado, E.M., Hardy, J.A. Description: Phosphorylation regulates assembly of the caspase-6 substrate-binding gr... |
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==Phosphorylation regulates assembly of the caspase-6 substrate-binding groove== | |||
<StructureSection load='3s8e' size='340' side='right'caption='[[3s8e]], [[Resolution|resolution]] 2.88Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3s8e]] is a 8 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=3S8E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S8E FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.88Å</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=3s8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s8e OCA], [https://pdbe.org/3s8e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s8e RCSB], [https://www.ebi.ac.uk/pdbsum/3s8e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s8e ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CASP6_HUMAN CASP6_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Caspases, a family of apoptotic proteases, are increasingly recognized as being extensively phosphorylated, usually leading to inactivation. To date, no structural mechanism for phosphorylation-based caspase inactivation is available, although this information may be key to achieving caspase-specific inhibition. Caspase-6 has recently been implicated in neurodegenerative conditions including Huntington's and Alzheimer's diseases. A full understanding of caspase-6 regulation is crucial to caspase-6-specific inhibition. Caspase-6 is phosphorylated by ARK5 kinase at serine 257 leading to suppression of cell death via caspase-6 inhibition. Our structure of the fully inactive phosphomimetic S257D reveals that phosphorylation results in a steric clash with P201 in the L2' loop. Removal of the proline side chain alleviates the clash resulting in nearly wild-type activity levels. This phosphomimetic-mediated steric clash causes misalignment of the substrate-binding groove, preventing substrate binding. Substrate-binding loop misalignment appears to be a widely used regulatory strategy among caspases and may present a new paradigm for caspase-specific control. | |||
Phosphorylation regulates assembly of the caspase-6 substrate-binding groove.,Velazquez-Delgado EM, Hardy JA Structure. 2012 Apr 4;20(4):742-51. Epub 2012 Apr 3. PMID:22483120<ref>PMID:22483120</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3s8e" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Caspase 3D structures|Caspase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Hardy JA]] | |||
[[Category: Velazquez-Delgado EM]] | |||
Latest revision as of 20:23, 1 November 2023
Phosphorylation regulates assembly of the caspase-6 substrate-binding groovePhosphorylation regulates assembly of the caspase-6 substrate-binding groove
Structural highlights
FunctionCASP6_HUMAN Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. Publication Abstract from PubMedCaspases, a family of apoptotic proteases, are increasingly recognized as being extensively phosphorylated, usually leading to inactivation. To date, no structural mechanism for phosphorylation-based caspase inactivation is available, although this information may be key to achieving caspase-specific inhibition. Caspase-6 has recently been implicated in neurodegenerative conditions including Huntington's and Alzheimer's diseases. A full understanding of caspase-6 regulation is crucial to caspase-6-specific inhibition. Caspase-6 is phosphorylated by ARK5 kinase at serine 257 leading to suppression of cell death via caspase-6 inhibition. Our structure of the fully inactive phosphomimetic S257D reveals that phosphorylation results in a steric clash with P201 in the L2' loop. Removal of the proline side chain alleviates the clash resulting in nearly wild-type activity levels. This phosphomimetic-mediated steric clash causes misalignment of the substrate-binding groove, preventing substrate binding. Substrate-binding loop misalignment appears to be a widely used regulatory strategy among caspases and may present a new paradigm for caspase-specific control. Phosphorylation regulates assembly of the caspase-6 substrate-binding groove.,Velazquez-Delgado EM, Hardy JA Structure. 2012 Apr 4;20(4):742-51. Epub 2012 Apr 3. PMID:22483120[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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