6gy5
From Proteopedia
Crystal structure of the kelch domain of human KLHL20 in complex with DAPK1 peptide
Structural highlights
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 PubMedBTB-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. References
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Categories: Human | Large Structures | Arrowsmith, C H | Bountra, C | Bullock, A N | Burgess-Brown, N | Carpenter, E P | Chen, Z | Cooper, C D.O | Delft, F von | Edwards, A M | Fairhead, M | Hozjan, V | Johansson, C | Krojer, T | Mathea, S | Pike, A C.W | Sanvitale, C E | Sorrell, F | Srikannathasan, V | Strain-Damerell, C | Wang, D | Williams, E | Complex | Death domain | E3 ligase | Kelch domain | Ligase | Substrate | Ubiquitination
