ArticleOpen biology2020
Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12.
Article in Open biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
- Review
- Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment.Nature communications · 2025Article
- Review
- FaSTPACE: a fast and scalable tool for peptide alignment and consensus extraction.NAR genomics and bioinformatics · 2024Article
- MEF2B C-terminal mutations enhance transcriptional activity and stability to drive B cell lymphomagenesis.Nature communications · 2024Article
- A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development.Nature communications · 2023Article
- [Lactate-induced up-regulation of PLEKHA4 promotes proliferation and apoptosis of human glioma cells].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2023Article
- Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase.The Biochemical journal · 2022Article
- Co-adaptor driven assembly of a CUL3 E3 ligase complex.Molecular cell · 2022Article
- The roles of KLHL family members in human cancers.American journal of cancer research · 2022Review
- LZTR1: A promising adaptor of the CUL3 family.Oncology letters · 2021Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
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.
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