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Structural basis of sugar recognition by SCFFBS2 ubiquitin ligase involved in NGLY1 deficiency

Author

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

Abstract

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 SCFFBS2 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, Man3GlcNAc2, 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.

DOI: 10.1002/1873-3468.15003