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==Cryo-EM structure of the RAF activating complex KSR-MEK-CNK-HYP==
<StructureSection load='8bw9' size='340' side='right'caption='[[8bw9]], [[Resolution|resolution]] 3.32&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8bw9]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8BW9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BW9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.32&#8491;</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=QOM:Trametinib'>QOM</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=8bw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bw9 OCA], [https://pdbe.org/8bw9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bw9 RCSB], [https://www.ebi.ac.uk/pdbsum/8bw9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bw9 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AVE_DROME AVE_DROME] Required for normal photoreceptor differentiation between Ras and Raf for EGFR signaling in the eye and for mitogen-activated protein kinase phosphorylation. Probably acts together with Cnk to promote Raf activation, perhaps by recruiting an activating kinase.
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== Publication Abstract from PubMed ==
The RAS-MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and the kinases RAF, MEK and ERK. Activation of RAF by RAS is notoriously intricate and remains only partially understood. There are three RAF isoforms in mammals (ARAF, BRAF and CRAF) and two related pseudokinases (KSR1 and KSR2). RAS-mediated activation of RAF depends on an allosteric mechanism driven by the dimerization of its kinase domain. Recent work on human RAFs showed that MEK binding to KSR1 promotes KSR1-BRAF heterodimerization, which leads to the phosphorylation of free MEK molecules by BRAF. Similar findings were made with the single Drosophila RAF homolog. Here we show that the fly scaffold proteins CNK and HYP stabilize the KSR-MEK interaction, which in turn enhances RAF-KSR heterodimerization and RAF activation. The cryogenic electron microscopy structure of the minimal KSR-MEK-CNK-HYP complex reveals a ring-like arrangement of the CNK-HYP complex allowing CNK to simultaneously engage KSR and MEK, thus stabilizing the binary interaction. Together, these results illuminate how CNK contributes to RAF activation by stimulating the allosteric function of KSR and highlight the diversity of mechanisms impacting RAF dimerization as well as the regulatory potential of the KSR-MEK interaction.

The CNK-HYP scaffolding complex promotes RAF activation by enhancing KSR-MEK interaction.,Maisonneuve P, Sahmi M, Bergeron-Labrecque F, Ma XI, Queguiner J, Arseneault G, Lefrancois M, Kurinov I, Fronzes R, Sicheri F, Therrien M Nat Struct Mol Biol. 2024 Jul;31(7):1028-1038. doi: 10.1038/s41594-024-01233-6. , Epub 2024 Feb 22. PMID:38388830<ref>PMID:38388830</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8bw9" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Drosophila melanogaster]]
[[Category: Large Structures]]
[[Category: Fronzes R]]
[[Category: Maisonneuve P]]
[[Category: Sicheri F]]