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Structural basis for recruitment of DAPK1 to the KLHL20 E3 ligase

DOI: 10.1016/j.str.2019.06.005 DOI Help

Authors: Zhuoyao Chen (Structural Genomics Consortium, University of Oxford) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Panagis Filippakopoulos (Structural Genomics Consortium, University of Oxford) , Vincenzo D'Angiolella (Cancer Research UK and Medical Research Council Institute for Radiation Oncology, University of Oxford) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: July 2019
Diamond Proposal Number(s): 15433

Open Access Open Access

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 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.

Journal Keywords: BTB; ubiquitination; Cullin-RING ligase; crystallography; CUL3; protein-protein interaction; cancer; autophagy

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 16/07/2019 09:35

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)