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==Crystal structure of the kelch domain of human KLHL12 in complex with DVL1 peptide==
<StructureSection load='6ttk' size='340' side='right'caption='[[6ttk]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ttk]] 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=6TTK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TTK 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]] 2.383&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=6ttk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ttk OCA], [https://pdbe.org/6ttk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ttk RCSB], [https://www.ebi.ac.uk/pdbsum/6ttk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ttk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KLH12_HUMAN KLH12_HUMAN] Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a negative regulator of Wnt signaling pathway and ER-Golgi transport (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B) (PubMed:22358839, PubMed:27565346). The BCR(KLHL12) complex is also involved in neural crest specification: in response to cytosolic calcium increase, interacts with the heterodimer formed with PEF1 and PDCD6/ALG-2, leading to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export (PubMed:27716508). As part of the BCR(KLHL12) complex, also acts as a negative regulator of the Wnt signaling pathway by mediating ubiquitination and subsequent proteolysis of DVL3 (PubMed:16547521). The BCR(KLHL12) complex also mediates polyubiquitination of DRD4 and PEF1, without leading to degradation of these proteins (PubMed:18303015, PubMed:20100572, PubMed:27716508).<ref>PMID:16547521</ref> <ref>PMID:18303015</ref> <ref>PMID:20100572</ref> <ref>PMID:22358839</ref> <ref>PMID:27565346</ref> <ref>PMID:27716508</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Wnt signalling is dependent on dishevelled proteins (DVL1-3), which assemble an intracellular Wnt signalosome at the plasma membrane. The levels of DVL1-3 are regulated by multiple Cullin-RING E3 ligases that mediate their ubiquitination and degradation. The BTB-Kelch protein KLHL12 was the first E3 ubiquitin ligase to be identified for DVL1-3, but the molecular mechanisms determining its substrate interactions have remained unknown. Here, we mapped the interaction of DVL1-3 to a 'PGXPP' motif that is conserved in other known partners and substrates of KLHL12, including PLEKHA4, PEF1, SEC31 and DRD4. To determine the binding mechanism, we solved a 2.4 A crystal structure of the Kelch domain of KLHL12 in complex with a DVL1 peptide that bound with low micromolar affinity. The DVL1 substrate adopted a U-shaped turn conformation that enabled hydrophobic interactions with all six blades of the Kelch domain beta-propeller. In cells, the mutation or deletion of this motif reduced the binding and ubiquitination of DVL1 and increased its stability confirming this sequence as a degron motif for KLHL12 recruitment. These results define the molecular mechanisms determining DVL regulation by KLHL12 and establish the KLHL12 Kelch domain as a new protein interaction module for a novel proline-rich motif.

Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12.,Chen Z, Wasney GA, Picaud S, Filippakopoulos P, Vedadi M, D'Angiolella V, Bullock AN Open Biol. 2020 Jun;10(6):200041. doi: 10.1098/rsob.200041. Epub 2020 Jun 24. PMID:32574548<ref>PMID:32574548</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ttk" style="background-color:#fffaf0;"></div>

==See Also==
*[[Kelch-like protein 3D structures|Kelch-like protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Bullock AN]]
[[Category: Burgess-Brown N]]
[[Category: Chalk R]]
[[Category: Chen Z]]
[[Category: Edwards AM]]
[[Category: Krojer T]]
[[Category: Pike ACW]]
[[Category: Strain-Damerell C]]
[[Category: Wang D]]
[[Category: Williams E]]
[[Category: Von Delft F]]