Molecular basis of cullin-3 (Cul3) ubiquitin ligase subversion by vaccinia virus protein A55

The Journal of Biological Chemistry
C. GaoStephen C Graham

Abstract

BTB-Kelch proteins are substrate-specific adaptors for cullin-3 (Cul3) RING-box-based E3 ubiquitin ligases, mediating protein ubiquitylation for subsequent proteasomal degradation. Vaccinia virus encodes three BTB-Kelch proteins: A55, C2, and F3. Viruses lacking A55 or C2 have altered cytopathic effects in cultured cells and altered pathology in vivo Previous studies have shown that the ectromelia virus orthologue of A55 interacts with Cul3 in cells. We report that the N-terminal BTB-BACK (BB) domain of A55 binds directly to the Cul3 N-terminal domain (Cul3-NTD), forming a 2:2 complex in solution. We solved the structure of an A55BB/Cul3-NTD complex from anisotropic crystals diffracting to 2.3/3.7 Å resolution in the best/worst direction, revealing that the overall interaction and binding interface closely resemble the structures of cellular BTB/Cul3-NTD complexes, despite low sequence identity between A55 and cellular BTB domains. Surprisingly, despite this structural similarity, the affinity of Cul3-NTD for A55BB was stronger than for cellular BTB proteins. Glutamate substitution of the A55 residue Ile-48, adjacent to the canonical φX(D/E) Cul3-binding motif, reduced affinity of A55BB for Cul3-NTD by at least 2 orders of magn...Continue Reading

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Citations

Feb 27, 2020·The Journal of General Virology·Sarah NeidelGeoffrey L Smith
Aug 29, 2021·Pathogens·Sian Lant, Carlos Maluquer de Motes

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Methods Mentioned

BETA
co-immunoprecipitation
tandem affinity purification
immunoprecipitation
co-IP
light-scattering
Isothermal titration calorimetry
thermal
PCR
transfection
gel-filtration

Software Mentioned

PDBePISA
Prism7
DIALS
Clustal Omega
ISOLDE
PHENIX PHASER - MR
STARANISO
GraphPad
MicroCal PEAQ - ITC
Molprobity

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