Structure and dynamics of the ASB9 CUL-RING E3 Ligase

Ryan J. Lumpkin, Richard W. Baker, Andres E. Leschziner and Elizabeth A. Komives ()
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Ryan J. Lumpkin: University of California, San Diego
Richard W. Baker: University of California, San Diego
Andres E. Leschziner: University of California, San Diego
Elizabeth A. Komives: University of California, San Diego

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16499-9

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