Structural basis of sugar recognition by SCF FBS2 ubiquitin ligase involved in NGLY1 deficiency.
Tadashi SatohMaho Yagi-UtsumiNozomi IshiiTsunehiro MizushimaHirokazu YagiRyuichi KatoYuriko TachidaHiroaki TatenoIchiro MatsuoKoichi KatoTadashi SuzukiYukiko YoshidaPublished in: FEBS letters (2024)
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.
Keyphrases
- structural basis
- quality control
- endoplasmic reticulum
- protein protein
- binding protein
- replacement therapy
- electronic health record
- big data
- dna damage
- high resolution
- emergency department
- transcription factor
- human health
- dna repair
- amino acid
- machine learning
- risk assessment
- small molecule
- gene expression
- copy number
- mass spectrometry
- data analysis
- climate change
- drug induced
- case control
- artificial intelligence