2vpj

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Crystal structure of the Kelch domain of human KLHL12

Structural highlights

2vpj is a 1 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 1.85Å
Ligands:ACT
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Cullin-RING ligases (CRLs) are multi-subunit E3 ubiquitin ligases that recruit substrate-specific adaptors to catalyze protein ubiquitylation. Cul3-based CRLs are uniquely associated with BTB adaptors that incorporate homodimerization, Cul3 assembly and substrate recognition into a single multi-domain protein, of which the best known are BTB-BACK-Kelch domain proteins including KEAP1. Cul3 assembly requires a BTB protein 3-box motif, analogous to the F-box and SOCS box motifs of other Cullin-based E3s. To define the molecular basis for this assembly and the overall architecture of the E3 we determined the crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3, along with the Kelch domain structures of KLHL2 (Mayven), KLHL7, KLHL12 and KBTBD5. We show that Cul3 interaction is dependent on an unique N-terminal extension sequence that packs against the 3-box in a hydrophobic groove centrally located between the BTB and BACK domains. Deletion of this N-terminal region results in a 30-fold loss in affinity. The presented data offer a model for the quaternary assembly of this E3 class that supports the bivalent capture of Nrf2 and reveals potential new sites for E3 inhibitor design.

Structural basis for Cul3 assembly with the BTB-Kelch family of E3 ubiquitin ligases.,Canning P, Cooper CD, Krojer T, Murray JW, Pike AC, Chaikuad A, Keates T, Thangaratnarajah C, Hojzan V, Marsden BD, Gileadi O, Knapp S, von Delft F, Bullock AN J Biol Chem. 2013 Jan 24. PMID:23349464[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. ↑ Canning P, Cooper CD, Krojer T, Murray JW, Pike AC, Chaikuad A, Keates T, Thangaratnarajah C, Hojzan V, Marsden BD, Gileadi O, Knapp S, von Delft F, Bullock AN. Structural basis for Cul3 assembly with the BTB-Kelch family of E3 ubiquitin ligases. J Biol Chem. 2013 Jan 24. PMID:23349464 doi:http://dx.doi.org/10.1074/jbc.M112.437996

Contents


PDB ID 2vpj

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