6TTK

Crystal structure of the kelch domain of human KLHL12 in complex with DVL1 peptide

Summary for 6TTK

• Entry DOI: 10.2210/pdb6ttk/pdb
• Descriptor: Kelch-like protein 12, DVL1, SODIUM ION, ... (6 entities in total)
• Functional Keywords: cullin3 e3 ligase, kelch, complex, substrate peptide, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 137511.49

Authors

Chen, Z.,Williams, E.,Pike, A.C.W.,Strain-Damerell, C.,Wang, D.,Chalk, R.,Burgess-Brown, N.,Krojer, T.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.N. (deposition date: 2019-12-27, release date: 2020-02-12, Last modification date: 2024-01-24)

Primary citation

Chen, Z.,Wasney, G.A.,Picaud, S.,Filippakopoulos, P.,Vedadi, M.,D'Angiolella, V.,Bullock, A.N.
Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12.
Open Biology, 10:200041-200041, 2020

PubMed Abstract: 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 Å 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 β-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.

PubMed: 32574548
DOI: 10.1098/rsob.200041

Experimental method

X-RAY DIFFRACTION (2.383 Å)