6ttk

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

Structural highlights

6ttk is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.383Å
Ligands:CL, EDO, NA
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).[1] [2] [3] [4] [5] [6]

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[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Angers S, Thorpe CJ, Biechele TL, Goldenberg SJ, Zheng N, MacCoss MJ, Moon RT. The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation. Nat Cell Biol. 2006 Apr;8(4):348-57. doi: 10.1038/ncb1381. Epub 2006 Mar 19. PMID:16547521 doi:http://dx.doi.org/10.1038/ncb1381
  2. ↑ Rondou P, Haegeman G, Vanhoenacker P, Van Craenenbroeck K. BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase. J Biol Chem. 2008 Apr 25;283(17):11083-96. doi: 10.1074/jbc.M708473200. Epub 2008, Feb 26. PMID:18303015 doi:http://dx.doi.org/10.1074/jbc.M708473200
  3. ↑ Rondou P, Skieterska K, Packeu A, Lintermans B, Vanhoenacker P, Vauquelin G, Haegeman G, Van Craenenbroeck K. KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation. Cell Signal. 2010 Jun;22(6):900-13. doi: 10.1016/j.cellsig.2010.01.014. Epub 2010, Jan 25. PMID:20100572 doi:http://dx.doi.org/10.1016/j.cellsig.2010.01.014
  4. ↑ Jin L, Pahuja KB, Wickliffe KE, Gorur A, Baumgartel C, Schekman R, Rape M. Ubiquitin-dependent regulation of COPII coat size and function. Nature. 2012 Feb 22;482(7386):495-500. doi: 10.1038/nature10822. PMID:22358839 doi:http://dx.doi.org/10.1038/nature10822
  5. ↑ Scott DC, Rhee DY, Duda DM, Kelsall IR, Olszewski JL, Paulo JA, de Jong A, Ovaa H, Alpi AF, Harper JW, Schulman BA. Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation. Cell. 2016 Aug 25;166(5):1198-1214.e24. doi: 10.1016/j.cell.2016.07.027. PMID:27565346 doi:http://dx.doi.org/10.1016/j.cell.2016.07.027
  6. ↑ McGourty CA, Akopian D, Walsh C, Gorur A, Werner A, Schekman R, Bautista D, Rape M. Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor. Cell. 2016 Oct 6;167(2):525-538.e14. doi: 10.1016/j.cell.2016.09.026. PMID:27716508 doi:http://dx.doi.org/10.1016/j.cell.2016.09.026
  7. ↑ Chen Z, Wasney GA, Picaud S, Filippakopoulos P, Vedadi M, D'Angiolella V, Bullock AN. Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12. Open Biol. 2020 Jun;10(6):200041. doi: 10.1098/rsob.200041. Epub 2020 Jun 24. PMID:32574548 doi:http://dx.doi.org/10.1098/rsob.200041

Contents


PDB ID 6ttk

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