Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase.
Adaptor Proteins, Signal Transducing
/ chemistry
Binding Sites
Crystallography, X-Ray
Death-Associated Protein Kinases
/ chemistry
Female
HEK293 Cells
Humans
Hydrophobic and Hydrophilic Interactions
Models, Molecular
Protein Binding
Protein Domains
Protein Structure, Secondary
Proteolysis
Ubiquitination
BTB
CUL3
Cullin-RING ligase
autophagy
cancer
crystallography
protein-protein interaction
ubiquitination
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
03 09 2019
03 09 2019
Historique:
received:
16
08
2018
revised:
26
05
2019
accepted:
03
06
2019
pubmed:
8
7
2019
medline:
19
5
2020
entrez:
8
7
2019
Statut:
ppublish
Résumé
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-Å 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 β 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 β-propeller domains versus linear grooves and suggests a new target for structure-based drug design.
Identifiants
pubmed: 31279627
pii: S0969-2126(19)30204-7
doi: 10.1016/j.str.2019.06.005
pmc: PMC6720452
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
KLHL20 protein, human
0
DAPK1 protein, human
EC 2.7.11.1
Death-Associated Protein Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1395-1404.e4Subventions
Organisme : Medical Research Council
ID : MR/N010051/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00001/7
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5255/A18085
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106169/ZZ14/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.
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