8avo
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8avo]] is a 6 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=8AVO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AVO FirstGlance]. <br> | <table><tr><td colspan='2'>[[8avo]] is a 6 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=8AVO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AVO FirstGlance]. <br> | ||
| - | </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=8avo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8avo OCA], [https://pdbe.org/8avo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8avo RCSB], [https://www.ebi.ac.uk/pdbsum/8avo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8avo ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 6.84Å</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=8avo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8avo OCA], [https://pdbe.org/8avo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8avo RCSB], [https://www.ebi.ac.uk/pdbsum/8avo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8avo ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling. | The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling. | ||
| - | Mechanism of receptor assembly via the pleiotropic adipokine Leptin.,Tsirigotaki A, Dansercoer A, Verschueren KHG, Markovic I, Pollmann C, Hafer M, Felix J, Birck C, Van Putte W, Catteeuw D, Tavernier J, Fernando Bazan J, Piehler J, Savvides SN, Verstraete K Nat Struct Mol Biol. 2023 | + | Mechanism of receptor assembly via the pleiotropic adipokine Leptin.,Tsirigotaki A, Dansercoer A, Verschueren KHG, Markovic I, Pollmann C, Hafer M, Felix J, Birck C, Van Putte W, Catteeuw D, Tavernier J, Fernando Bazan J, Piehler J, Savvides SN, Verstraete K Nat Struct Mol Biol. 2023 Apr;30(4):551-563. doi: 10.1038/s41594-023-00941-9. , Epub 2023 Mar 23. PMID:36959263<ref>PMID:36959263</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8avo" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8avo" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Human leptin in complex with the human LEP-R ectodomain fused to a C-terminal trimeric isoleucine GCN4 zipper (open 3:3 model).
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