Structural basis of sugar recognition by <scp> SCF <sup>FBS2</sup> </scp> ubiquitin ligase involved in <scp>NGLY1</scp> deficiency
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<sup>FBS2</sup> 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<sub>3</sub>GlcNAc<sub>2</sub>, 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.
Authors
- Ryuichi Kato (ORCID: https://orcid.org/0000-0003-2087-2896)
- Ichiro Matsuo (ORCID: https://orcid.org/0000-0003-0740-1184)
- Yukiko Yoshida (ORCID: https://orcid.org/0000-0002-0629-0219)
- Maho Yagi‐Utsumi (ORCID: https://orcid.org/0000-0001-8144-740X)
- Koichi Kato (ORCID: https://orcid.org/0000-0001-7187-9612)
- Tadashi Satoh (ORCID: https://orcid.org/0000-0002-4493-4978)
- Tadashi Suzuki (ORCID: https://orcid.org/0000-0003-1030-7631)
- Tsunehiro Mizushima (ORCID: https://orcid.org/0000-0002-6631-2889)
- Nozomi Ishii (ORCID: https://orcid.org/0000-0002-4678-7393)
- Hirokazu Yagi (ORCID: https://orcid.org/0000-0001-9296-0225)
- Hiroaki Tateno (ORCID: https://orcid.org/0000-0003-3006-1659)
- Yuriko Tachida
Institutions
- High Energy Accelerator Research Organization (JP)
- Gunma University (JP)
- University of Hyogo (JP)
- National Institutes of Natural Sciences (JP)
- Kiryu University (JP)
- Nagoya City University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Pioneer (Japan) (JP)
- Institute for Molecular Science (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
Publication Details
- Journal
- FEBS Letters
- Published
- 2024-08-22
- DOI
- https://doi.org/10.1002/1873-3468.15003
- Citations
- 2
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 1.15
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Canadian Glycomics Network
- Institute for Protein Research, Osaka University
- Core Research for Evolutional Science and Technology
- Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences