6gy5

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Crystal structure of the kelch domain of human KLHL20 in complex with DAPK1 peptide

Structural highlights

6gy5 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:CL, EDO, NA
Gene:KLHL20, KLEIP, KLHLX (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KLH20_HUMAN] Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in interferon response and anterograde Golgi to endosome transport. The BCR(KLHL20) E3 ubiquitin ligase complex mediates the ubiquitination of DAPK1, leading to its degradation by the proteasome, thereby acting as a negative regulator of apoptosis (PubMed:20389280). The BCR(KLHL20) E3 ubiquitin ligase complex also specifically mediates 'Lys-33'-linked ubiquitination (PubMed:24768539). Involved in anterograde Golgi to endosome transport by mediating 'Lys-33'-linked ubiquitination of CORO7, promoting interaction between CORO7 and EPS15, thereby facilitating actin polymerization and post-Golgi trafficking (PubMed:24768539). Also acts as a regulator of endothelial migration during angiogenesis by controlling the activation of Rho GTPases. The BCR(KLHL20) E3 ubiquitin ligase complex acts as a regulator of neurite outgrowth by mediating ubiquitination and degradation of PDZ-RhoGEF/ARHGEF11 (PubMed:21670212). In case of tumor, the BCR(KLHL20) E3 ubiquitin ligase complex is involved in tumor hypoxia: following hypoxia, the BCR(KLHL20)complex mediates ubiquitination and degradation of PML, potentiating HIF-1 signaling and cancer progression (PubMed:21840486).[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

BTB-Kelch proteins form the largest subfamily of Cullin-RING E3 ligases, yet their substrate complexes are mapped and structurally characterized only for KEAP1 and KLHL3. KLHL20 is a related CUL3-dependent ubiquitin ligase linked to autophagy, cancer, and Alzheimer's disease that promotes the ubiquitination and degradation of substrates including DAPK1, PML, and ULK1. We identified an "LPDLV"-containing motif in the DAPK1 death domain that determines its recruitment and degradation by KLHL20. A 1.1-A crystal structure of a KLHL20 Kelch domain-DAPK1 peptide complex reveals DAPK1 binding as a loose helical turn that inserts deeply into the central pocket of the Kelch domain to contact all six blades of the beta propeller. Here, KLHL20 forms salt-bridge and hydrophobic interactions including tryptophan and cysteine residues ideally positioned for covalent inhibitor development. The structure highlights the diverse binding modes of beta-propeller domains versus linear grooves and suggests a new target for structure-based drug design.

Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase.,Chen Z, Picaud S, Filippakopoulos P, D'Angiolella V, Bullock AN Structure. 2019 Jul 3. pii: S0969-2126(19)30204-7. doi:, 10.1016/j.str.2019.06.005. PMID:31279627[7]

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

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Citations
3 reviews cite this structure
E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones.
Ishida et al. (2021)
2 more
4 other articles
No citations found

References

  1. ↑ Furukawa M, He YJ, Borchers C, Xiong Y. Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol. 2003 Nov;5(11):1001-7. Epub 2003 Oct 5. PMID:14528312 doi:10.1038/ncb1056
  2. ↑ Nacak TG, Alajati A, Leptien K, Fulda C, Weber H, Miki T, Czepluch FS, Waltenberger J, Wieland T, Augustin HG, Kroll J. The BTB-Kelch protein KLEIP controls endothelial migration and sprouting angiogenesis. Circ Res. 2007 Apr 27;100(8):1155-63. doi: 10.1161/01.RES.0000265844.56493.ac., Epub 2007 Mar 29. PMID:17395875 doi:http://dx.doi.org/10.1161/01.RES.0000265844.56493.ac
  3. ↑ Lee YR, Yuan WC, Ho HC, Chen CH, Shih HM, Chen RH. The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses. EMBO J. 2010 May 19;29(10):1748-61. doi: 10.1038/emboj.2010.62. Epub 2010 Apr 13. PMID:20389280 doi:http://dx.doi.org/10.1038/emboj.2010.62
  4. ↑ Lin MY, Lin YM, Kao TC, Chuang HH, Chen RH. PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth. J Cell Biol. 2011 Jun 13;193(6):985-94. doi: 10.1083/jcb.201103015. PMID:21670212 doi:http://dx.doi.org/10.1083/jcb.201103015
  5. ↑ Yuan WC, Lee YR, Huang SF, Lin YM, Chen TY, Chung HC, Tsai CH, Chen HY, Chiang CT, Lai CK, Lu LT, Chen CH, Gu DL, Pu YS, Jou YS, Lu KP, Hsiao PW, Shih HM, Chen RH. A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell. 2011 Aug 16;20(2):214-28. doi: 10.1016/j.ccr.2011.07.008. PMID:21840486 doi:http://dx.doi.org/10.1016/j.ccr.2011.07.008
  6. ↑ Yuan WC, Lee YR, Lin SY, Chang LY, Tan YP, Hung CC, Kuo JC, Liu CH, Lin MY, Xu M, Chen ZJ, Chen RH. K33-Linked Polyubiquitination of Coronin 7 by Cul3-KLHL20 Ubiquitin E3 Ligase Regulates Protein Trafficking. Mol Cell. 2014 May 22;54(4):586-600. doi: 10.1016/j.molcel.2014.03.035. Epub 2014, Apr 24. PMID:24768539 doi:http://dx.doi.org/10.1016/j.molcel.2014.03.035
  7. ↑ Chen Z, Picaud S, Filippakopoulos P, D'Angiolella V, Bullock AN. Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase. Structure. 2019 Jul 3. pii: S0969-2126(19)30204-7. doi:, 10.1016/j.str.2019.06.005. PMID:31279627 doi:http://dx.doi.org/10.1016/j.str.2019.06.005

Contents


PDB ID 6gy5

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