Structural highlights
Function
FBX6_BOVIN Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complexes. Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation. Able to recognize and bind denatured glycoproteins, which are modified with not only high-mannose but also complex-type oligosaccharides. Also recognizes sulfated glycans. Also involved in DNA damage response by specifically recognizing activated CHEK1 (phosphorylated on 'Ser-345'), promoting its ubiquitination and degradation. Ubiquitination of CHEK1 is required to ensure that activated CHEK1 does not accumulate as cells progress through S phase, or when replication forks encounter transient impediments during normal DNA replication (By similarity).
Publication Abstract from PubMed
The cytosolic peptide:N-glycanase (PNGase) is involved in the quality control of N-glycoproteins via the endoplasmic reticulum-associated degradation (ERAD) pathway. Mutations in the gene encoding cytosolic PNGase (NGLY1 in humans) cause NGLY1 deficiency. Recent findings indicate that the F-box protein FBS2 of the SCF(FBS2) ubiquitin ligase complex can be a promising drug target for NGLY1 deficiency. Here, we determined the crystal structure of bovine FBS2 complexed with the adaptor protein SKP1 and a sugar ligand, Man(3)GlcNAc(2), which corresponds to the core pentasaccharide of N-glycan. Our crystallographic data together with NMR data revealed the structural basis of disparate sugar-binding specificities in homologous FBS proteins and identified a potential druggable pocket for in silico docking studies. Our results provide a potential basis for the development of selective inhibitors against FBS2 in NGLY1 deficiency.
Structural basis of sugar recognition by SCF(FBS2) ubiquitin ligase involved in NGLY1 deficiency.,Satoh T, Yagi-Utsumi M, Ishii N, Mizushima T, Yagi H, Kato R, Tachida Y, Tateno H, Matsuo I, Kato K, Suzuki T, Yoshida Y FEBS Lett. 2024 Aug 22. doi: 10.1002/1873-3468.15003. PMID:39171510[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Satoh T, Yagi-Utsumi M, Ishii N, Mizushima T, Yagi H, Kato R, Tachida Y, Tateno H, Matsuo I, Kato K, Suzuki T, Yoshida Y. Structural basis of sugar recognition by SCF(FBS2) ubiquitin ligase involved in NGLY1 deficiency. FEBS Lett. 2024 Aug 22. PMID:39171510 doi:10.1002/1873-3468.15003
