Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase.
Structure
; 27(9): 1395-1404.e4, 2019 09 03.
Article
em En
| MEDLINE
| ID: mdl-31279627
ABSTRACT
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 ß 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 ß-propeller domains versus linear grooves and suggests a new target for structure-based drug design.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Adaptadoras de Transdução de Sinal
/
Proteínas Quinases Associadas com Morte Celular
Limite:
Female
/
Humans
Idioma:
En
Revista:
Structure
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido