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Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases.

Canning P, Cooper CDO, Krojer T, Murray JW, Pike ACW, Chaikuad A, Keates T, Thangaratnarajah C, Hojzan V, Marsden BD, Gileadi O, Knapp S, von Delft F, Bullock AN
J Biol Chem 288 7803-7814 (2013)
Related entries: 2xn4, 3ii7, 4ap2, 4apf, 4asc

Cited: 145 times
EuropePMC logo PMID: 23349464

Abstract

Cullin-RING ligases are multisubunit E3 ubiquitin ligases that recruit substrate-specific adaptors to catalyze protein ubiquitylation. Cul3-based Cullin-RING ligases are uniquely associated with BTB adaptors that incorporate homodimerization, Cul3 assembly, and substrate recognition into a single multidomain protein, of which the best known are BTB-BACK-Kelch domain proteins, including KEAP1. Cul3 assembly requires a BTB protein "3-box" motif, analogous to the F-box and SOCS box motifs of other Cullin-based E3s. To define the molecular basis for this assembly and the overall architecture of the E3, we determined the crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3, along with the Kelch domain structures of KLHL2 (Mayven), KLHL7, KLHL12, and KBTBD5. We show that Cul3 interaction is dependent on a unique N-terminal extension sequence that packs against the 3-box in a hydrophobic groove centrally located between the BTB and BACK domains. Deletion of this N-terminal region results in a 30-fold loss in affinity. The presented data offer a model for the quaternary assembly of this E3 class that supports the bivalent capture of Nrf2 and reveals potential new sites for E3 inhibitor design.

Reviews - 2vpj mentioned but not cited (1)

  1. Drug resistance genomics of the antimalarial drug artemisinin. Winzeler EA, Manary MJ. Genome Biol 15 544 (2014)

Articles - 2vpj mentioned but not cited (11)

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  2. Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. Canning P, Cooper CDO, Krojer T, Murray JW, Pike ACW, Chaikuad A, Keates T, Thangaratnarajah C, Hojzan V, Marsden BD, Gileadi O, Knapp S, von Delft F, Bullock AN. J Biol Chem 288 7803-7814 (2013)
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Reviews citing this publication (45)

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