4asc
Crystal structure of the Kelch domain of human KBTBD5
Structural highlights
DiseaseKLH40_HUMAN Severe congenital nemaline myopathy. The disease is caused by variants affecting the gene represented in this entry. FunctionKLH40_HUMAN Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a key regulator of skeletal muscle development (PubMed:23746549). The BCR(KLHL40) complex acts by mediating ubiquitination and degradation of TFDP1, thereby regulating the activity of the E2F:DP transcription factor complex (By similarity). Promotes stabilization of LMOD3 by acting as a negative regulator of LMOD3 ubiquitination; the molecular process by which it negatively regulates ubiquitination of LMOD3 is however unclear (By similarity).[UniProtKB:Q9D783][1] Publication Abstract from PubMedCullin-RING ligases (CRLs) are multi-subunit E3 ubiquitin ligases that recruit substrate-specific adaptors to catalyze protein ubiquitylation. Cul3-based CRLs are uniquely associated with BTB adaptors that incorporate homodimerization, Cul3 assembly and substrate recognition into a single multi-domain 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 an 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. Structural basis for Cul3 assembly with the BTB-Kelch family of E3 ubiquitin ligases.,Canning P, Cooper CD, Krojer T, Murray JW, Pike AC, Chaikuad A, Keates T, Thangaratnarajah C, Hojzan V, Marsden BD, Gileadi O, Knapp S, von Delft F, Bullock AN J Biol Chem. 2013 Jan 24. PMID:23349464[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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