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| | ==Crystal structure of the mouse RIP3-MLKL complex== | | ==Crystal structure of the mouse RIP3-MLKL complex== |
| - | <StructureSection load='4m69' size='340' side='right' caption='[[4m69]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='4m69' size='340' side='right'caption='[[4m69]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4m69]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M69 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M69 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4m69]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M69 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M69 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4m69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m69 OCA], [https://pdbe.org/4m69 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m69 RCSB], [https://www.ebi.ac.uk/pdbsum/4m69 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m69 ProSAT]</span></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4m66|4m66]], [[4m68|4m68]]</td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ripk3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), Mlkl ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=4m69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m69 OCA], [http://pdbe.org/4m69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4m69 RCSB], [http://www.ebi.ac.uk/pdbsum/4m69 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4m69 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RIPK3_MOUSE RIPK3_MOUSE]] Essential for programmed necrosis in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity).<ref>PMID:19590578</ref> [[http://www.uniprot.org/uniprot/MLKL_MOUSE MLKL_MOUSE]] Required for the execution of programmed necrosis (By similarity). | + | [https://www.uniprot.org/uniprot/RIPK3_MOUSE RIPK3_MOUSE] Essential for programmed necrosis in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity).<ref>PMID:19590578</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: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Mus musculus]] |
| - | [[Category: Peng, W]] | + | [[Category: Peng W]] |
| - | [[Category: Shi, Y]] | + | [[Category: Shi Y]] |
| - | [[Category: Wu, J]] | + | [[Category: Wu J]] |
| - | [[Category: Xie, T]] | + | [[Category: Xie T]] |
| - | [[Category: Yan, C]] | + | [[Category: Yan C]] |
| - | [[Category: Kinase]]
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| - | [[Category: Phosphorylation]]
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| - | [[Category: Transferase-signaling protein complex]]
| + | |
| Structural highlights
4m69 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
RIPK3_MOUSE Essential for programmed necrosis in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity).[1]
Publication Abstract from PubMed
RIP3 is an essential upstream kinase in necroptosis. The pseudokinase MLKL functions as a substrate of RIP3 to mediate downstream signaling. The molecular mechanism by which RIP3 recognizes and phosphorylates MLKL remains unknown. Here, we report the crystal structures of the mouse RIP3 kinase domain, the MLKL kinase-like domain, and a binary complex between the two. Both RIP3 and MLKL adopt the canonical kinase fold. Free RIP3 exists in an active conformation, whereas MLKL-bound RIP3 is stabilized by AMP-PNP to adopt an inactive conformation. The formation of the RIP3-MLKL complex, involving their respective N- and C-lobes, is accompanied by pronounced conformational changes of the alphaC helix and activation loop in RIP3 and the corresponding structural elements in MLKL. RIP3-mediated MLKL phosphorylation, though important for downstream signaling, is dispensable for stable complex formation between RIP3 and MLKL. Our study serves as a framework for mechanistic understanding of RIP3-mediated necroptotic signaling.
Structural Insights into RIP3-Mediated Necroptotic Signaling.,Xie T, Peng W, Yan C, Wu J, Gong X, Shi Y Cell Rep. 2013 Oct 17;5(1):70-8. doi: 10.1016/j.celrep.2013.08.044. Epub 2013 Oct, 3. PMID:24095729[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep. 2009 Aug;10(8):916-22. doi: 10.1038/embor.2009.109. Epub 2009 Jul 10. PMID:19590578 doi:http://dx.doi.org/10.1038/embor.2009.109
- ↑ Xie T, Peng W, Yan C, Wu J, Gong X, Shi Y. Structural Insights into RIP3-Mediated Necroptotic Signaling. Cell Rep. 2013 Oct 17;5(1):70-8. doi: 10.1016/j.celrep.2013.08.044. Epub 2013 Oct, 3. PMID:24095729 doi:http://dx.doi.org/10.1016/j.celrep.2013.08.044
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