Structure and dynamics of the ASB9 CUL-RING E3 Ligase.
The Cullin 5 (CUL5) Ring E3 ligase uses adaptors Elongins B and C (ELOB/C) to bind different SOCS-box-containing substrate receptors, determining the substrate specificity of the ligase. The 18-member ankyrin and SOCS box (ASB) family is the largest substrate receptor family. Here we report cryo-EM data for the substrate, creatine ... kinase (CKB) bound to ASB9-ELOB/C, and for full-length CUL5 bound to the RING protein, RBX2, which binds various E2s. To date, no full structures are available either for a substrate-bound ASB nor for CUL5. Hydrogen-deuterium exchange (HDX-MS) mapped onto a full structural model of the ligase revealed long-range allostery extending from the substrate through CUL5. We propose a revised allosteric mechanism for how CUL-E3 ligases function. ASB9 and CUL5 behave as rigid rods, connected through a hinge provided by ELOB/C transmitting long-range allosteric crosstalk from the substrate through CUL5 to the RBX2 flexible linker.
Mesh Terms:
Allosteric Regulation, Creatine Kinase, Cryoelectron Microscopy, Cullin Proteins, Elongin, Humans, Models, Molecular, Protein Binding, Protein Subunits, Structure-Activity Relationship, Substrate Specificity, Suppressor of Cytokine Signaling Proteins, Ubiquitin-Protein Ligases
Allosteric Regulation, Creatine Kinase, Cryoelectron Microscopy, Cullin Proteins, Elongin, Humans, Models, Molecular, Protein Binding, Protein Subunits, Structure-Activity Relationship, Substrate Specificity, Suppressor of Cytokine Signaling Proteins, Ubiquitin-Protein Ligases
Nat Commun
Date: Dec. 08, 2019
PubMed ID: 32513959
View in: Pubmed Google Scholar
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