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Structure of BACH1 BTB domain-bound FBXL17 ubiquitin ligase
Structural highlights
FunctionFXL17_HUMAN Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex, a key component of a quality control pathway required to ensure functional dimerization of BTB domain-containing proteins (dimerization quality control, DQC) (PubMed:30190310). FBXL17 specifically recognizes and binds a conserved degron of non-consecutive residues present at the interface of BTB dimers of aberrant composition: aberrant BTB dimer are then ubiquitinated by the SCF(FBXL17) complex and degraded by the proteasome (PubMed:30190310). The ability of the SCF(FBXL17) complex to eliminate compromised BTB dimers is required for the differentiation and survival of neural crest and neuronal cells (By similarity). The SCF(FBXL17) complex mediates ubiquitination and degradation of BACH1 (PubMed:24035498, PubMed:30190310). The SCF(FBXL17) complex is also involved in the regulation of the hedgehog/smoothened (Hh) signaling pathway by mediating the ubiquitination and degradation of SUFU, allowing the release of GLI1 from SUFU for proper Hh signal transduction (PubMed:27234298). The SCF(FBXL17) complex mediates ubiquitination and degradation of PRMT1 (By similarity).[UniProtKB:B1H1X1][UniProtKB:Q9QZN1][1] [2] [3] Publication Abstract from PubMedThe transcription factor BACH1 regulates heme homeostasis and oxidative stress responses and promotes cancer metastasis upon aberrant accumulation. Its stability is controlled by two F-box protein ubiquitin ligases, FBXO22 and FBXL17. Here we show that the homodimeric BTB domain of BACH1 functions as a previously undescribed quaternary structure degron, which is deciphered by the two F-box proteins via distinct mechanisms. After BACH1 is released from chromatin by heme, FBXO22 asymmetrically recognizes a cross-protomer interface of the intact BACH1 BTB dimer, which is otherwise masked by the co-repressor NCOR1. If the BACH1 BTB dimer escapes the surveillance by FBXO22 due to oxidative modifications, its quaternary structure integrity is probed by a pair of FBXL17, which simultaneously engage and remodel the two BTB protomers into E3-bound monomers for ubiquitination. By unveiling the multifaceted regulatory mechanisms of BACH1 stability, our studies highlight the abilities of ubiquitin ligases to decode high-order protein assemblies and reveal therapeutic opportunities to block cancer invasion via compound-induced BACH1 destabilization. Distinct Perception Mechanisms of BACH1 Quaternary Structure Degrons by Two F-box Proteins under Oxidative Stress.,Cao S, Shi H, Garcia SF, Kito Y, Shi H, Goldberg HV, Ponce J, Ueberheide B, Lignitto L, Pagano M, Zheng N bioRxiv [Preprint]. 2024 Jun 3:2024.06.03.594717. doi: 10.1101/2024.06.03.594717. PMID:38895309[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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