Kelch repeat and BTB domain-containing protein 4 (KBTBD4)

Kelch repeat and BTB domain-containing protein 4 (KBTBD4) is a substrate receptor component of the CULLIN3-RING E3 ubiquitin ligase complex, responsible for recruiting substrates for ubiquitination and subsequent proteasomal degradation. The protein contains an N-terminal BTB (Broad-Complex, Tramtrack, and Bric-à-brac) domain, a BACK (BTB and C-terminal Kelch) domain, and a C-terminal Kelch-repeat β-propeller domain critical for protein-protein interactions. In cancer, especially medulloblastoma, recurrent neomorphic mutations in KBTBD4's Kelch domain enable aberrant degradation of the transcriptional corepressor CoREST complex (RCOR1, LSD1/KDM1A, and HDAC1/2) by altering the substrate specificity of the E3 ligase, a process that can also be induced by the molecular glue UM171. These gain-of-function mutations are mechanistically linked to disease progression and represent both a therapeutic vulnerability and a molecular paradigm for drug-induced neosubstrate targeting by E3 ligase complexes.

Other names

BKLHD4FLJ10450HSPC252BTB and kelch domain-containing protein 4kelch repeat and BTB (POZ) domain-containing protein 4

UM171: Promotes neomorphic substrate recruitment to KBTBD4, mimicking cancer gain-of-function mutations, driving degradation of HDAC1/2-CoREST complexes. HDAC1/2 inhibitors: Block mutant KBTBD4 binding to its neosubstrate and inhibit proliferation of KBTBD4-mutant cancer cells